0122: The serotonergic system in pathological human cardiac valves. What is the role of progenitors cells expressing the 5-HT2B receptor?

Many compounds (pergolide, cabergoline, fenfluramine, ectasy) were described as inducers of fibrotic valvular lesions, a rare but severe drug reaction. All these drugs share in common the pharmacological property to activate a serotonergic receptor subtype, the 5HT2B. Together with the well known “carcinoid heart” that is a valvulopathy due to high amounts of circulating serotonin, these observations lead to the hypothesis that cardiac valves express a “serotonergic system” that could be activated by 5-HT or 5-HTR agonists. The aim of this work was to characterize the pattern of expression of 5-HT2A,2B,4 receptors, the serotonin transporter (SERT) and the biosynthesis peripheral enzyme (Tph1) in various valvulopathies. Thirty degenerated human valves were collected: 11 calcified aortic valves (CAV), 5 sclerotic aortic valves (SAV), 11 dystrophic mitral valves (DMV). They were analyzed by RT-qPCR and immunohistochemistery. All samples express 5HT2A,2B,4 receptors, SERT and Tph1. In these valve tissues, the amount of 5HT2B receptor (5HT2B R) mRNA is higher than the 5HT2A one (5HT2A R) : Δ Ct (5HT2B R -18S) = 12,53±1,12 vs Δ Ct (5HT2A R -18S) = 15,95±2,37 for CAV, Δ Ct (5HT2B R -18S) = 13,04±2,62 vs Δ Ct (5HT2A R - 18S)=16,00±1,46 for SAV, Δ Ct (5HT2B R -18S) = 12,34±0,77 vs Δ Ct (5HT2A R -18S) = 16,14±0,86 for DMV. The amounts of SERT, Tph1 and 5HT4 receptor mRNA are negligible whatever valve and etiology. At a topographical point of view, 5HT2BR expression is found in endothelial cells (at the valve surface) but also inside valve lesions, by interstitial cells (smooth muscle α-actin and vimentin positive cells) located in an abundant glycosaminoglycan matrix. Characterization of these cells is in progress. In particular, we characterize the high amount CD34+ hematopoietic progenitors that are highly present in fibromyxoid lesions. To summarize, 5HT2A,2B,4 receptors, SERT and Tph1 are expressed in aortic and mitral diseased valves. The amounts of 5HT2A,2B R mRNA are equal between mitral and aortic valves. The contribution of the two 5-HT2 receptors in valve degeneration is now under investigation whatever the pathological process considered

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

Background/introductionCurrently, 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.PurposeTo 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.MethodsPatients 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.ResultsWe 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).ConclusionIn 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

L'assistance ventriculaire en pont à la transplantation cardiaque dans le traitement du choc cardiogénique (Evaluation d'une stratégie thérapeutique)

STRASBOURG-Medecine (674822101) / SudocSudocFranceF

Assistance circulatoire en intention de transplantation (Greffe cardiaque après assistance circulatoire. Etude rétrospective bicentrique concernant 50 observations.)

STRASBOURG-Medecine (674822101) / SudocSudocFranceF

Ischémie-reperfusion des membres (Effets protecteurs ou délétères des pré- et post-conditionnements ischémiques)

L ischémie aiguë des membres inférieurs, suivie d une reperfusion, présente de lourdes conséquences. Ce travail s intéresse aux effets délétères locaux et à distance de l ischémiereperfusion (IR) des muscles squelettiques des rongeurs, ainsi qu aux effets protecteurs ou délétères des pré et postconditionnement ischémiques. Nos différentes études montrent que l IR entraîne une altération de la fonction des complexes I, II, III, et IV de la chaîne respiratoire mitochondriale du muscle squelettique ainsi qu une altération de la fonction du complexe I au niveau pulmonaire, et une surexpression des complexes I et II au niveau rénal. L IR entraîne également une apoptose accrue et une accumulation des radicaux libres de l oxygène (RLO) au niveau musculaire squelettique. Le préconditionnement ischémique (IPC) local ou à distance empêche l altération du complexe I, et protège partiellement les complexes II et III. L efficacité de l IPC local ou à distance est similaire. Les ARNm de l apoptose ne sont pas surexprimés après IPC local ou à distance. Le postconditionnement ischémique (PoC) a un effet délétère sur le muscle squelettique, qu il soit local ou à distance. Il y a également une accumulation accrue de RLO après PoC, témoignant de leur effet délétère. L altération de la chaîne respiratoire mitochondriale pulmonaire par l IR musculaire squelettique est vraisemblablement due à l accumulation de leucocytes et leur activation au niveau du parenchyme pulmonaire. La stimulation de l activité mitochondriale rénale après IR musculaire squelettique pourrait permettre une meilleure épuration des produits ischémiques libérés dans la circulation systémique lors de la reperfusion.Peripheral arterial acute ischemic events, followed by reperfusion, have devastating consequences. Our studies stressed local and remote deleterious effects of skeletal muscle ischemiareperfusion (IR) in rodents, along with the protective or deleterious effects of ischemic pre and postconditioning. We proved that IR causes mitochondrial respiratory chain complexes I, II, III and IV dysfunction, pulmonary complex I dysfunction, and renal complexes I and II enhancement. We also proved that IR caused skeletal muscle apoptosis, and produced increased amounts of reactive oxygen species (ROS). Local and remote ischemic preconditioning (IPC) restored skeletal muscle mitochondrial respiratory chain complex I function, and partially protected complexes II and III. Local and remote preconditioning are similarly efficient. Apoptosis mRNA were not overproduced after local or remote IPC. Ischemic postconditioning (PoC) has deleterious effects on skeletal muscles, whether it was local or remote. After PoC, more ROS are produced, proving their deleterious effects. Pulmonary mitochondrial respiratory chain dysfunction secondary to skeletal muscle IR is most likely due to leukocyte sequestration and activation in the lung parenchyma. Renal mitochondrial pulmonary chain enhancement after skeletal muscle IR may help in renal blood detoxification of skeletal muscle ischemic products that was released in the systemic blood stream during reperfusion.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Virulence of beta-hemolytic streptococci in infective endocarditis

BACKGROUND: Streptococci involved in infective endocarditis (IE) primarily comprise alpha- or non-hemolytic streptococci (ANHS). Moreover, beta-hemolytic streptococci (BHS) can be involved, and guidelines recommend the addition of gentamicin for the first 2 weeks of treatment and the consideration of early surgery in such cases. This study compared the morbidity and mortality associated with IE depending on the microorganisms involved (BHS, ANHS, staphylococci, and enterococci).METHODS: We conducted a retrospective observational study between 2012 and 2017 in a single hospital in France. The endpoints were overall in-hospital mortality, 1-year mortality and the occurrence of complications.RESULTS: We analyzed 316 episodes of definite IE including 150 (38%), 96 (25%), 46 (12%), and 24 cases (6%) of staphylococcal, ANHS, enterococcal, and BHS IE, respectively. In-hospital mortality was significantly higher in the staphylococcal (n = 40; 26.7%) and BHS groups (n = 6; 25.0%) than in the ANHS (n = 9; 9.4%) and enterococcal groups (n = 5; 10.9%) (all p < 0.01). The rates of septic shock and cerebral emboli were also higher in the BHS group than in the ANHS group [n = 7 (29.2%) vs. n = 3 (3.1%), p < 0.001; n = 7 (29.2%) vs. n = 12 (12.5%); p = 0.05, respectively].CONCLUSION: This study confirmed that BHS IE has a more severe prognosis than ANHS IE. The virulence of BHS may be similar to that of staphylococci, justifying increased monitoring of these patients and more 'aggressive' treatments such as early surgery

Remote and local ischemic postconditioning further impaired skeletal muscle mitochondrial function after ischemia-reperfusion

Muscular injuries contribute to perioperative and long-term morbidity after vascular surgery in humans. We determined whether local and remote ischemic postconditioning might similarly decrease muscle mitochondrial dysfunction through reduced oxidative stress.; Eighteen male Black-6 mice were divided in three groups: (1) sham mice had no ischemia (sham), (2) ischemia-reperfusion (IR) mice underwent 2-hour tourniquet-induced ischemia on both hind limbs, followed by 2-hour reperfusion, and (3) postconditioning (PoC) mice underwent four bouts of 30-second reperfusion and 30-second ischemia at the onset of reperfusion on the right limb; thus, the right limb underwent local PoC and left limb underwent remote PoC (rPoC). Maximal oxidative capacity (V(max)) of the gastrocnemius muscle mitochondrial respiratory chain was measured. Oxidative stress was evaluated by dihydroethidium staining. Expressions of genes involved in antioxidant defense (superoxide dismutase [SOD1], SOD2, glutathione peroxidase [GPx]), apoptosis (Bax, BclII), and inflammation (interleukin-6) were determined by quantitative real-time polymerase chain reaction. Muscle inflammation was determined using immunohistochemistry.; IR reduced V(max) (8.5 ± 2.2 vs 10.2 ± 1.8 μmol O(2)/min/g dry weight; P = .034), and increased dihydroethidium staining (134.8%; P = .039). IR decreased GPx expression (-47.9%; P = .048) and increased the proapoptotic marker Bax (255.5%; P = .020). Local PoC and rPoC further increased these deleterious effects. PoC decreased V(max) to 4.4 ± 1.4 μmol O(2)/min/g dry weight (sham vs PoC, -56.9% [P < .001]; IR vs PoC, -48.2% [P < .001]). rPoC similarly reduced V(max) to 5.1 ± 1.9 μmol O(2)/min/g dry weight (sham vs PoC, -50.0% [P < .001]; IR vs PoC, -40.0% [P = .001]). Dihydroethidium staining was further increased by PoC (207.2%; P = .002) and rPoC (305.4%; P < .001) compared with sham and was associated with macrophage infiltration. Local PoC increased SOD1, SOD2, and the antiapoptotic Bcl-2, and rPoC increased Bax (391.6%; P < .001) and the Bax/BclII ratio (621.7%; P < .001).; Local and remote ischemic postconditioning further increased injury by enhancing mitochondrial dysfunction, oxidative stress production, and inflammation. Caution should be applied when considering ischemic postconditioning in vascular surgery

EPA:DHA 6:1 is a superior omega-3 PUFAs formulation attenuating platelets-induced contractile responses in porcine coronary and human internal mammary artery by targeting the serotonin pathway via an increased endothelial formation of nitric oxide

International audienceAt arterial sites of endothelial denudation and dysfunction, activated platelets contribute to vascular injury through the release of potent contracting factors such as serotonin (5-HT). This study evaluated whether omega-3 polyunsaturated fatty acids (PUFAs), known to protect the vascular system, are able to prevent platelets-induced contractile responses in isolated arteries and, if so, to investigate the underlying mechanism and the importance of the omega-3 PUFAs formulation. Porcine coronary arteries (PCA), human internal mammary arteries (IMA) and washed human platelets were prepared and vascular reactivity was studied in organ chambers. In PCA rings, aggregating platelets caused concentration-dependent contractions that were significantly inhibited by the 5-HT2A receptor antagonist ketanserin, and by EPA:DHA 6:1 but not EPA:DHA 1:1 at 0.4% v/v. EPA:DHA 6:1 also prevented the 5-HT-induced contractions but affected only slightly those to the thromboxane A2 analogue U46619. The inhibitory effect of EPA:DHA 6:1 on platelets-induced contractions was not observed in rings without endothelium, and prevented by an eNOS inhibitor but not by inhibitors of endothelium-dependent hyperpolarization. In IMA rings, EPA:DHA 6:1 but not EPA:DHA 1:1 at 0.4% v/v significantly prevented the 5-HT-induced contraction, and induced greater endothelium-dependent relaxations than bradykinin and acetylcholine sensitive to an eNOS inhibitor. EPA:DHA 6:1 strongly inhibits platelets- and 5-HT-induced contractions in PCA rings and those to 5-HT in IMA rings most likely through an increased endothelial formation of NO. These findings suggest that the omega-3 PUFAs EPA:DHA 6:1 formulation may be of interest to prevent platelets-induced vascular injury at arterial sites of endothelial dysfunction