Julien Amour

Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipo-fibrokines

AIMS Recent studies have reported a relationship between the abundance of epicardial adipose tissue (EAT) and the risk of cardiovascular diseases including atrial fibrillation (AF). However, the underlying mechanisms are unknown. The aim of this study was to examine the effects of the secretome of human EAT on the histological properties of the myocardium. METHODS AND RESULTS Samples of EAT and subcutaneous adipose (SAT), obtained from 39 patients undergoing coronary bypass surgery, were analysed and tested in an organo-culture model of rat atria to evaluate the fibrotic properties of human fat depots. The EAT secretome induced global fibrosis (interstitial and peripheral) of rat atria in organo-culture conditions. Activin A was highly expressed in EAT compared with SAT and promoted atrial fibrosis, an effect blocked using neutralizing antibody. In addition, Activin A levels were enhanced in patients with low left-ventricular function. In sections of human atrial and ventricular myocardium, adipose and myocardial tissues were in close contact, together with fibrosis. CONCLUSION This study provides the first evidence that the secretome from EAT promotes myocardial fibrosis through the secretion of adipo-fibrokines such as Activin A.

Intra-aortic balloon pump effects on macrocirculation and microcirculation in cardiogenic shock patients supported by venoarterial extracorporeal membrane oxygenation

Objectives:This study was designed to assess the effects on macrocirculation and microcirculation of adding an intra-aortic balloon pump to peripheral venoarterial extracorporeal membrane oxygenation in patients with severe cardiogenic shock and little/no residual left ventricular ejection. Design:A prospective, single-center, observational study where macrocirculation and microcirculation were assessed with clinical-, Doppler echocardiography–, and pulmonary artery–derived hemodynamic variables and also cerebral and thenar eminence tissue oxygenation and side-stream dark-field imaging of sublingual microcirculation. Setting:A 26-bed tertiary ICU in a university hospital. Patients:We evaluated 12 consecutive patients before and 30 minutes after interrupting and restarting intra-aortic balloon pump. Interventions:Measurements were performed before, and 30 minutes after interrupting and restarting intra-aortic balloon pump. Measurements and Main Results:Stopping intra-aortic balloon pump was associated with higher pulmonary artery-occlusion pressure (19 ± 10 vs 15 ± 8 mm Hg, p = 0.01), increased left ventricular end-systolic (51 ± 13 vs 50 ± 14 mm, p = 0.05) and end-diastolic (55 ± 13 vs 52 ± 14 mm, p = 0.003) dimensions, and decreased pulse pressure (15 ± 13 vs 29 ± 22 mm Hg, p = 0.02). Maximum pulmonary artery-occlusion pressure reduction when the intra-aortic balloon pump was restarted was observed in the seven patients whose pulmonary artery-occlusion pressure was more than 15 mm Hg when intra-aortic balloon pump was off (–6.6 ± 4.3 vs –0.6 ± 3.4 mm Hg, respectively). Thenar eminence and brain tissue oxygenation and side-stream dark-field–assessed sublingual microcirculation were unchanged by stopping and restarting intra-aortic balloon pump. Conclusions:Restoring pulsatility and decreasing left ventricular afterload with intra-aortic balloon pump was associated with smaller left ventricular dimensions and lower pulmonary artery pressures but did not affect microcirculation variables in cardiogenic shock patients with little/no residual left ventricular ejection while on peripheral venoarterial extracorporeal membrane oxygenation.

Human epicardial adipose tissue has a specific transcriptomic signature depending on its anatomical peri-atrial, peri-ventricular, or peri-coronary location

AIMS Human epicardial adipose tissue (EAT) is a visceral and perivascular fat that has been shown to act locally on myocardium, atria, and coronary arteries. Its abundance has been linked to coronary artery disease (CAD) and atrial fibrillation. However, its physiological function remains highly debated. The aim of this study was to determine a specific EAT transcriptomic signature, depending on its anatomical peri-atrial (PA), peri-ventricular (PV), or peri-coronary location. METHODS AND RESULTS Samples of EAT and thoracic subcutaneous fat, obtained from 41 patients paired for cardiovascular risk factors, CAD, and atrial fibrillation were analysed using a pangenomic approach. We found 2728 significantly up-regulated genes in the EAT vs. subcutaneous fat with 400 genes being common between PA, PV, and peri-coronary EAT. These common genes were related to extracellular matrix remodelling, inflammation, infection, and thrombosis pathways. Omentin (ITLN1) was the most up-regulated gene and secreted adipokine in EAT (fold-change >12, P < 0.0001). Among EAT-enriched genes, we observed different patterns depending on adipose tissue location. A beige expression phenotype was found in EAT but PV EAT highly expressed uncoupled protein 1 (P = 0.01). Genes overexpressed in peri-coronary EAT were implicated in proliferation, O-N glycan biosynthesis, and sphingolipid metabolism. PA EAT displayed an atypical pattern with genes implicated in cardiac muscle contraction and intracellular calcium signalling pathway. CONCLUSION This study opens new perspectives in understanding the physiology of human EAT and its local interaction with neighbouring structures.

Effect of Levosimendan on Low Cardiac Output Syndrome in Patients With Low Ejection Fraction Undergoing Coronary Artery Bypass Grafting With Cardiopulmonary Bypass: The LICORN Randomized Clinical Trial

Importance Low cardiac output syndrome after cardiac surgery is associated with high morbidity and mortality in patients with impaired left ventricular function. Objective To assess the ability of preoperative levosimendan to prevent postoperative low cardiac output syndrome. Design, Setting, and Participants Randomized, double-blind, placebo-controlled trial conducted in 13 French cardiac surgical centers. Patients with a left ventricular ejection fraction less than or equal to 40% and scheduled for isolated or combined coronary artery bypass grafting with cardiopulmonary bypass were enrolled from June 2013 until May 2015 and followed during 6 months (last follow-up, November 30, 2015). Interventions Patients were assigned to a 24-hour infusion of levosimendan 0.1 µg/kg/min (n = 167) or placebo (n = 168) initiated after anesthetic induction. Main Outcomes and Measures Composite end point reflecting low cardiac output syndrome with need for a catecholamine infusion 48 hours after study drug initiation, need for a left ventricular mechanical assist device or failure to wean from it at 96 hours after study drug initiation when the device was inserted preoperatively, or need for renal replacement therapy at any time postoperatively. It was hypothesized that levosimendan would reduce the incidence of this composite end point by 15% in comparison with placebo. Results Among 336 randomized patients (mean age, 68 years; 16% women), 333 completed the trial. The primary end point occurred in 87 patients (52%) in the levosimendan group and 101 patients (61%) in the placebo group (absolute risk difference taking into account center effect, −7% [95% CI, −17% to 3%]; P = .15). Predefined subgroup analyses found no interaction with ejection fraction less than 30%, type of surgery, and preoperative use of &bgr;-blockers, intra-aortic balloon pump, or catecholamines. The prevalence of hypotension (57% vs 48%), atrial fibrillation (50% vs 40%), and other adverse events did not significantly differ between levosimendan and placebo. Conclusions and Relevance Among patients with low ejection fraction who were undergoing coronary artery bypass grafting with cardiopulmonary bypass, levosimendan compared with placebo did not result in a significant difference in the composite end point of prolonged catecholamine infusion, use of left ventricular mechanical assist device, or renal replacement therapy. These findings do not support the use of levosimendan for this indication. Trial Registration EudraCT Number: 2012-000232-25; clinicaltrials.gov Identifier: NCT02184819

Efficacy of Ex Vivo Autologous and In Vivo Platelet Transfusion in the Reversal of P2Y12 Inhibition by Clopidogrel, Prasugrel, and Ticagrelor The APTITUDE Study

Background—Allogenic platelet transfusions (PT) are administered to treat excessive bleeding in patients on P2Y12 receptor inhibitors (RI). We assessed the effect of ex vivo and in vivo PT on platelet activation and aggregation in patients on dual antiplatelet therapy. Methods and Results—In the Antagonize P2Y12 Treatment Inhibitors by Transfusion of Platelets in an Urgent or Delayed Timing After Acute Coronary Syndrome or Percutaneous Coronary Intervention Presentation-Acute Coronary Syndrome (APTITUDE-ACS) study, patients presenting with acute coronary syndrome or for elective percutaneous coronary intervention, receiving loading doses of clopidogrel (600 mg, n=13 or 900 mg, n=12), prasugrel 60 mg (n=10), or ticagrelor 180 mg (n=10) were included. PT was performed ex vivo by mixing platelet-rich plasma from blood sampling performed at baseline in increasing proportions with platelet-rich plasma sampled 4 hours after loading dose. The percentage restoration of residual platelet aggregation achieved with 80% proportion PT (residual platelet aggregation 80% PT mix/residual platelet aggregation baseline×100) significantly decreased with increasing potency of P2Y12 RI (83.9±11%, 73±14%, 66.3±15%, 40.9±19% for clopidogrel 600 mg, clopidogrel 900 mg, prasugrel, and ticagrelor, respectively; P for trend <0.0001). In the APTITUDE-Coronary Artery Bypass Graft (APTITUDE-CABG) study, vasodilator-stimulated phosphoprotein-platelet reactivity index, a specific marker of the P2Y12 RI drug–effect, was assessed before and after in vivo PT administered for excessive bleeding in patients undergoing cardiac surgery while on a maintenance dose of aspirin and clopidogrel (n=45), prasugrel (n=6), or ticagrelor (n=3). When compared with baseline, there was a significant relative increase of 23.1% in platelet activation after PT transfusion (42.2±23.6% versus 56.6±18.2%; P=0.0008). Conclusions—PT restores platelet reactivity in patients with acute coronary syndrome/percutaneous coronary intervention and in patients undergoing cardiac surgery on P2Y12 RI while bleeding with a less effect with increasing potency of P2Y12 inhibition. Clinical Trial Registration—URL: http://www.recherche-biomedicale.sante.gouv.fr/pro/comites/coordonnees.htm and http://www.cnil.fr/. Unique identifiers: No. 301111 and No. 1547216v0.

Lateral Membrane-Specific MAGUK CASK Down-Regulates NaV1.5 Channel in Cardiac Myocytes

RATIONALE Mechanisms underlying membrane protein localization are crucial in the proper function of cardiac myocytes. The main cardiac sodium channel, NaV1.5, carries the sodium current (INa) that provides a rapid depolarizing current during the upstroke of the action potential. Although enriched in the intercalated disc, NaV1.5 is present in different membrane domains in myocytes and interacts with several partners. OBJECTIVE To test the hypothesis that the MAGUK (membrane-associated guanylate kinase) protein CASK (calcium/calmodulin-dependent serine protein kinase) interacts with and regulates NaV1.5 in cardiac myocytes. METHODS AND RESULTS Immunostaining experiments showed that CASK localizes at lateral membranes of cardiac myocytes, in association with dystrophin. Whole-cell patch clamp showed that CASK-silencing increases INa in vitro. In vivo CASK knockdown similarly increased INa recorded in freshly isolated myocytes. Pull-down experiments revealed that CASK directly interacts with the C-terminus of NaV1.5. CASK silencing reduces syntrophin expression without affecting NaV1.5 and dystrophin expression levels. Total Internal Reflection Fluorescence microscopy and biotinylation assays showed that CASK silencing increased the surface expression of NaV1.5 without changing mRNA levels. Quantification of NaV1.5 expression at the lateral membrane and intercalated disc revealed that the lateral membrane pool only was increased upon CASK silencing. The protein transport inhibitor brefeldin-A prevented INa increase in CASK-silenced myocytes. During atrial dilation/remodeling, CASK expression was reduced but its localization remained unchanged. CONCLUSION This study constitutes the first description of an unconventional MAGUK protein, CASK, which directly interacts with NaV1.5 channel and controls its surface expression at the lateral membrane by regulating ion channel trafficking.

Active Bleeding after Cardiac Surgery: A Prospective Observational Multicenter Study

Main Objectives To estimate the incidence of active bleeding after cardiac surgery (AB) based on a definition directly related on blood flow from chest drainage; to describe the AB characteristics and its management; to identify factors of postoperative complications. Methods AB was defined as a blood loss > 1.5 ml/kg/h for 6 consecutive hours within the first 24 hours or in case of reoperation for hemostasis during the first 12 postoperative hours. The definition was applied in a prospective longitudinal observational study involving 29 French centers; all adult patients undergoing cardiac surgery with cardiopulmonary bypass were included over a 3-month period. Perioperative data (including blood product administration) were collected. To study possible variation in clinical practice among centers, patients were classified into two groups according to the AB incidence of the center compared to the overall incidence: “Low incidence” if incidence is lower and “High incidence” if incidence is equal or greater than overall incidence. Logistic regression analysis was used to identify risk factors of postoperative complications. Results Among 4,904 patients, 129 experienced AB (2.6%), among them 52 reoperation. Postoperative bleeding loss was 1,000 [820;1,375] ml and 1,680 [1,280;2,300] ml at 6 and 24 hours respectively. Incidence of AB varied between centers (0 to 16%) but was independent of in-centre cardiac surgical experience. Comparisons between groups according to AB incidence showed differences in postoperative management. Body surface area, preoperative creatinine, emergency surgery, postoperative acidosis and red blood cell transfusion were risk factors of postoperative complication. Conclusions A blood loss > 1.5 ml/kg/h for 6 consecutive hours within the first 24 hours or early reoperation for hemostasis seems a relevant definition of AB. This definition, independent of transfusion, adjusted to body weight, may assess real time bleeding occurring early after surgery.

Arterial Pulsatility and Circulating von Willebrand Factor in Patients on Mechanical Circulatory Support

BACKGROUND The main risk factor for bleeding in patients with continuous-flow mechanical circulatory support (CF-MCS) is the acquired von Willebrand factor (VWF) defect related to the high shear-stress forces developed by these devices. Although a higher bleeding rate has been reported in CF-MCS recipients who had reduced pulsatility, the relation between pulsatility and the VWF defect has never been studied. OBJECTIVES The purpose of this study was to investigate the relation between pulsatility and VWF under CF-MCS. METHODS We assessed the effect of 2 CF-MCS on VWF multimer degradation in a mock circulatory loop (model 1). Using these devices, we investigated in a dose-effect model (model 2) 3 levels of pulsatility in 3 groups of swine. In a cross-over model (model 3), we studied the effects of sequential changes of pulsatility on VWF. We reported the evolution of VWF multimerization in a patient undergoing serial CF-MCS and/or pulsatile-MCS. RESULTS We demonstrated the proteolytic degradation of VWF multimers by high shear CF-MCS in a circulatory loop without pulsatility. We observed both in swine models and in a patient that the magnitude of the VWF degradation is modulated by the pulsatility level in the high shear-stress level condition, and that the restoration of pulsatility is a trigger for the endothelial release of VWF. CONCLUSIONS We demonstrated that the VWF defect reflects the balance between degradation induced by the shear stress and the endothelial release of new VWF triggered by the pulsatility. This modulation of VWF levels could explain the relationship between pulsatility and bleeding observed in CF-MCS recipients. Preservation of pulsatility may be a new target to improve clinical outcomes of patients.

Perioperative Management of the Patient with an Implantable Cardioverter Defibrillator

Patients suffering from arrhythmic, ischemic, or dilated cardiomyopathy are particularly exposed to the risk of sudden death from ventricular fibrillation [1–3]. In 2015, sudden cardiac death is responsible for 4,5 million death every year in the world [2, 3]. In this context, early defibrillation by electric shock offers the best chance of survival [2–5]. With over 500,000 sudden deaths a year in the North American continent alone, the number of cardiac defibrillators implanted has increased exponentially since 2005, especially after publication of different studies and meta-analyses showing the benefit of this treatment in terms of survival [5–7]. Thus 270,000 defibrillators were implanted worldwide in the year 2005 alone, of which 30% were in the USA.

Postoperative serum levels of Endocan are associated with the duration of norepinephrine support after coronary artery bypass surgery

BACKGROUND Cardiopulmonary bypass (CPB) is associated with a systemic inflammatory response and an endothelial dysfunction, whose qualitative assessment appears to be a major issue. Endocan (ESM-1, endothelial cell specific molecule-1) is a protein preferentially expressed by the endothelium and previously associated with prognosis of septic shock or acute respiratory distress syndrome. In this pilot study, we investigated the kinetic of Endocan in planned coronary artery bypass grafting (CABG) surgery with CPB. PATIENTS AND METHODS We conducted an observational, prospective, mono centre study. All adult patients with left systolic ejection fraction>50%, undergoing planned on-pump CABG, were screened for inclusion. A written informed consent was obtained. Measurements and main results Serum Endocan concentrations were respectively 2.4 [2.1-3.0] ng. mL-1, 10.4 [7.4-13.9] ng.mL-1, 5.7 [4.4-8.2] ng.mL-1, and 5.4 [4.1-7.5] ng.mL-1 at day 0, day 1, day 3 and day 5. Endocan concentrations increased at day 1, day 3, and day 5 in comparison with preoperative concentration (P<0.001). In the multivariate analysis, age (P=0.002), history of acute coronary syndrome (P=0.024) and the catecholamine-free days at day 28 (P=0.007) were associated to the increase of perioperative Endocan concentrations. CONCLUSION Serum Endocan concentration increases after CABG surgery with CPB until day 1. The norepinephrine support increases the risk of Endocan release, suggesting a relationship between the kinetic of Endocan and the vasoplegic syndrome. At day 3, Endocan concentration decreases slowly but is not normalised at day 5. Further studies should investigate the prognostic value of the magnitude of postoperative Endocan concentration after cardiac surgery.