The training-induced changes on automatism, conduction and myocardial refractoriness are not mediated by parasympathetic postganglionic neurons activity

The purpose of this study is to test the role that parasympathetic postganglionic neurons could play on the adaptive electrophysiological changes produced by physical training on intrinsic myocardial automatism, conduction and refractoriness. Trained rabbits were submitted to aphysical training protocol on treadmill during 6 weeks. The electrophysiological study was performed in an isolated heart preparation. The investigated myocardial properties were: (a) sinus automatism, (b) atrioventricular and ventriculoatrial conduction, (c) atrial, conduction system and ventricular refractoriness. The parameters to study the refractoriness were obtained by means of extrastimulus test at four diVerent pacing cycle lengths (10% shorter than spontaneous sinus cycle length, 250, 200 and 150 ms) and (d) mean dominant frequency (DF) of the induced ventricular Wbrillation (VF), using a spectral method. The electrophysiological protocol was performed before and during continuous atropine administration (1 ¿M), in order to block cholinergic receptors. Cholinergic receptor blockade did not modify either the increase in sinus cycle length, atrioventricular conduction and refractoriness (left ventricular and atrioventricular conduction system functional refractory periods) or the decrease of DF of VF. These Wndings reveal that the myocardial electrophysiological modiWcations produced by physical training are not mediated by intrinsic cardiac parasympathetic activity.The authors thank Carmen Rams, Ana Diaz, Pilar Navarro and Cesar Avellaneda for their excellent technical assistance. This work has been supported by grants from the Spanish Ministry of Education and Science (DEP2007-73234-C03-01) and Generalitat Valenciana (PROMETEO 2010/093). M Zarzoso was supported by a research scholarship from Generalitat Valenciana (BFPI/2008/003).Zarzoso Muñoz, M.; Such Miquel, L.; Parra Giraldo, G.; Brines Ferrando, L.; Such, L.; Chorro, F.; Guerrero, J.... (2012). The training-induced changes on automatism, conduction and myocardial refractoriness are not mediated by parasympathetic postganglionic neurons activity. European Journal of Applied Physiology. 112(6):2185-2193. https://doi.org/10.1007/s00421-011-2189-4S218521931126Armour JA, Hopkins DA (1990a) Activity of in vivo canine ventricular neurons. Am J Physiol Heart Circ Physiol 258:H326–H336. doi: 10.1152/ajpregu.00183.2004Armour JA, Hopkins DA (1990b) Activity of canine in situ left atrial ganglion neurons. Am J Physiol Heart Circ Physiol 259:H1207–H1215Armour JA (2004) Cardiac neuronal hierarchy in health and disease. Am J Physiol Regul Integr Comp Physiol 287:R262–R271Armour JA, Murphy DA, Yuan BX, Macdonald S, Hopkins DA (1997) Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat Rec 247:289–298Bedford TG, Tipton CM (1987) Exercise training and the arterial baroreflex. J Appl Physiol 63:1926–1932Bonaduce D, Petretta M, Cavallaro V, Apicella C, Ianniciello A, Romano M, Breglio R, Marciano F (1998) Intensive training and cardiac autonomic control in high level athletes. Med Sci Sports Exerc 30:691–696Brack KE, Coote JH, Ng GA (2011) Vagus nerve stimulation protects against ventricular fibrillation independent of muscarinic receptor activation. Cardiovasc Res 91:437–446. doi: 10.1093/cvr/cvr105Brorson L, Conradson TB, Olsson B, Varnauskas E (1976) Right atrial monophasic action potential and effective refractory periods in relation to physical training and maximal heart rate. Cardiovasc Res 10:160–168Carmeliet E, Mubagwa K (1998) Antiarrhythmic drugs and cardiac ion channels: mechanisms of action. Prog Biophys Mol Biol 70:1–72Chorro FJ, Cánoves J, Guerrero J, Mainar L, Sanchis J, Such L, López-Merino V (2000) Alteration of ventricular fibrillation by flecainide, verapamil, and sotalol: an experimental study. Circulation 101:1606–1615Di Carlo SE, Bishop VS (1990) Exercise training enhances cardiac afferent inhibition of baroreflex function. Am J Physiol 258:212–220Gagliardi M, Randall WC, Bieger D, Wurster RD, Hopkins DA, Armour JA (1988) Activity of in vivo canine cardiac plexus neurons. Am J Physiol Heart Circ Physiol 255:H789–H800Gao L, Wang W, Liu D, Zucker IH (2007) Exercise training normalizes sympathetic outflow by central antioxidant mechanisms in rabbits with pacing-induced chronic heart failure. Circulation 115:3095–3102. doi: 10.1161/CIRCULATIONAHA.106.677989Gaustad SE, Rolim N, Wisløff U (2010) A valid and reproducible protocol for testing maximal oxygen uptake in rabbits. Eur J Cardiovasc Prev Rehabil 17:83–88. doi: 10.1097/HJR.0b013e32833090c4Gómez-Cabrera MC, Borrás C, Pallardó FV, Sastre J, Ji LL, Viña J (2005) Decreasing xanthine oxidase-mediated oxidative stress prevents useful cellular adaptations to exercise in rats. J Physiol 567:113–120. doi: 10.1113/jphysiol.2004.080564Gray AL, Johnson TA, Ardell JL, Massari VJ (2004) Parasympathetic control of the heart II. A novel interganglionic intrinsic cardiac circuit mediates neural control of heart rate. J Appl Physiol 96:2273–2278. doi: 10.1152/japplphysiolHamilton KL, Powers SK, Sugiura T, Kim S, Lennon S, Tumer N, Mehta JL (2001) Short-term exercise training can improve myocardial tolerance to I/R without elevation in heat shock proteins. 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Perpendicular magnetic anisotropy in granular multilayers of COPD alloyed nanoparticles

Co-Pd multilayers obtained by Pd capping of pre-deposited Co nanoparticles on amorphous alumina are systematically studied by means of high-resolution transmission electron microscopy, x-ray diffraction, extended x-ray absorption fine structure, SQUID-based magnetometry, and x-ray magnetic circular dichroism. The films are formed by COPD alloyed nanoparticles self-organized across the layers, with the interspace between the nanoparticles filled by the non-alloyed Pd metal. The nanoparticles show atomic arrangements compatible with short-range chemical order of L10 strucure type. The collective magnetic behavior is that of ferromagnetically coupled particles with perpendicular magnetic anisotropy, irrespective of the amount of deposited Pd. For increasing temperature three magnetic phases are identified: hard ferromagnetic with strong coercive field, soft-ferromagnetic as in an amorphous asperomagnet, and superparamagnetic. Increasing the amount of Pd in the system leads to both magnetic hardness increment and higher transition temperatures. Magnetic total moments of 1.77(4) µB and 0.45(4) µB are found at Co and Pd sites, respectively, where the orbital moment of Co, 0.40(2) µB, is high, while that of Pd is negligible. The effective magnetic anisotropy is the largest in the capping metal series (Pd, Pt, W, Cu, Ag, Au), which is attributed to the interparticle interaction between de nanoparticles, in addition to the intraparticle anisotropy arising from hybridization between the 3d-4d bands associated to the Co and Pd chemical arrangement in a L10 structure type

Effect of chronic exercise on myocardial electrophysiological heterogeneity and stability. Role of intrinsic cholinergic neurons: A study in the isolated rabbit heart

[EN] A study has been made of the effect of chronic exercise on myocardial electrophysiological heterogeneity and stability, as well as of the role of cholinergic neurons in these changes. Determinations in hearts from untrained and trained rabbits on a treadmill were performed. The hearts were isolated and perfused. A pacing electrode and a recording multielectrode were located in the left ventricle. The parameters determined during induced VF, before and after atropine (1 mu M), were: fibrillatory cycle length (VV), ventricular functional refractory period (FRPVF), normalized energy (NE) of the fibrillatory signal and its coefficient of variation (CV), and electrical ventricular activation complexity, as an approach to myocardial heterogeneity and stability. The VV interval was longer in the trained group than in the control group both prior to atropine (78 +/- 10 vs. 68 +/- 10 ms) and after atropine (76 +/- 8 vs. 67 +/- 10 ms). Likewise, FRPVF was longer in the trained group than in the control group both prior to and after atropine (53 +/- 8 vs. 42 +/- 7 ms and 50 +/- 6 vs. 40 +/- 6 ms, respectively), and atropine did not modify FRPVF. The CV of FRPVF was lower in the trained group than in the control group prior to atropine (12.5 +/- 1.5% vs. 15.1 +/- 3.8%) and, decreased after atropine (15.1 +/- 3.8% vs. 12.2 +/- 2.4%) in the control group. The trained group showed higher NE values before (0.40 +/- 0.04 vs. 0.36 +/- 0.05) and after atropine (0.37 +/- 0.04 vs. 0.34 +/- 0.06; p = 0.08). Training decreased the CV of NE both before (23.3 +/- 2% vs. 25.2 +/- 4%; p = 0.08) and after parasympathetic blockade (22.6 +/- 1% vs. 26.1 +/- 5%). Cholinergic blockade did not modify these parameters within the control and trained groups. Activation complexity was lower in the trained than in the control animals before atropine (34 +/- 8 vs. 41 +/- 5), and increased after atropine in the control group (41 +/- 5 vs. 48 +/- 9, respectively). Thus, training decreases the intrinsic heterogeneity of the myocardium, increases electrophysiological stability, and prevents some modifications due to muscarinic block.This research was supported by the Spanish Ministry of Education and Science, (DEP2007-73234-C03-01 to AMA), http://www.mecd.gob.es/portada-mecd/; and the Generalitat Valenciana (PROMETEO 2010/093 to FJC, and FPI/2008/003 to MZ), http://www.gva.es/va/inicio/presentacion; jsessionid=ydprbDQZTsCTz85W1Such-Miquel, L.; Brines-Ferrando, L.; Alberola, A.; Zarzoso Muñoz, M.; Chorro Gasco, FJ.; Guerrero-Martínez, JF.; Parra-Giraldo, G.... (2018). Effect of chronic exercise on myocardial electrophysiological heterogeneity and stability. Role of intrinsic cholinergic neurons: A study in the isolated rabbit heart. 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(2011). The training-induced changes on automatism, conduction and myocardial refractoriness are not mediated by parasympathetic postganglionic neurons activity. European Journal of Applied Physiology, 112(6), 2185-2193. doi:10.1007/s00421-011-2189-4Billman, G. E. (2009). Cardiac autonomic neural remodeling and susceptibility to sudden cardiac death: effect of endurance exercise training. American Journal of Physiology-Heart and Circulatory Physiology, 297(4), H1171-H1193. doi:10.1152/ajpheart.00534.2009HAN, J., & MOE, G. K. (1964). Nonuniform Recovery of Excitability in Ventricular Muscle. Circulation Research, 14(1), 44-60. doi:10.1161/01.res.14.1.44Beaumont, E., Salavatian, S., Southerland, E. M., Vinet, A., Jacquemet, V., Armour, J. A., & Ardell, J. L. (2013). Network interactions within the canine intrinsic cardiac nervous system: implications for reflex control of regional cardiac function. The Journal of Physiology, 591(18), 4515-4533. doi:10.1113/jphysiol.2013.259382Armour, J. A. (2008). Potential clinical relevance of the ‘little brain’ on the mammalian heart. Experimental Physiology, 93(2), 165-176. doi:10.1113/expphysiol.2007.041178Abramochkin, D. V., Nurullin, L. F., Borodinova, A. A., Tarasova, N. V., Sukhova, G. S., Nikolsky, E. E., & Rosenshtraukh, L. V. (2009). Non-quantal release of acetylcholine from parasympathetic nerve terminals in the right atrium of rats. Experimental Physiology, 95(2), 265-273. doi:10.1113/expphysiol.2009.050302CHORRO, F. J., CANOVES, J., GUERRERO, J., MAINAR, L., SANCHIS, J., SORIA, E., … LOPEZ-MERINO, V. (2000). Opposite Effects of Myocardial Stretch and Verapamil on the Complexity of the Ventricular Fibrillatory Pattern: An Experimental Study. Pacing and Clinical Electrophysiology, 23(11), 1594-1603. doi:10.1046/j.1460-9592.2000.01594.xSuch, L., Rodriguez, A., Alberola, A., Lopez, L., Ruiz, R., Artal, L., … Chorro, F. J. (2002). 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Tissue Microenvironments Define and Get Reinforced by Macrophage Phenotypes in Homeostasis or during Inflammation, Repair and Fibrosis

Current macrophage phenotype classifications are based on distinct in vitro culture conditions that do not adequately mirror complex tissue environments. In vivo monocyte progenitors populate all tissues for immune surveillance which supports the maintenance of homeostasis as well as regaining homeostasis after injury. Here we propose to classify macrophage phenotypes according to prototypical tissue environments, e.g. as they occur during homeostasis as well as during the different phases of (dermal) wound healing. In tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce proinflammatory macrophages by Toll-like receptors or inflammasomes. Such classically activated macrophages contribute to further tissue inflammation and damage. Apoptotic cells and antiinflammatory cytokines dominate in postinflammatory tissues which induce macrophages to produce more antiinflammatory mediators. Similarly, tumor-associated macrophages also confer immunosuppression in tumor stroma. Insufficient parenchymal healing despite abundant growth factors pushes macrophages to gain a profibrotic phenotype and promote fibrocyte recruitment which both enforce tissue scarring. Ischemic scars are largely devoid of cytokines and growth factors so that fibrolytic macrophages that predominantly secrete proteases digest the excess extracellular matrix. Together, macrophages stabilize their surrounding tissue microenvironments by adapting different phenotypes as feed-forward mechanisms to maintain tissue homeostasis or regain it following injury. Furthermore, macrophage heterogeneity in healthy or injured tissues mirrors spatial and temporal differences in microenvironments during the various stages of tissue injury and repair. Copyright (C) 2012 S. Karger AG, Base

CA125-Guided Diuretic Treatment Versus Usual Care in Patients With Acute Heart Failure and Renal Dysfunction

Background: The optimal diuretic treatment strategy for patients with acute heart failure and renal dysfunction remains unclear. Plasma carbohydrate antigen 125 (CA125) is a surrogate of fluid overload and a potentially valuable tool for guiding decongestion therapy. The aim of this study was to determine if a CA125-guided diuretic strategy is superior to usual care in terms of short-term renal function in patients with acute heart failure and renal dysfunction at presentation. Methods: This multicenter, open-label study randomized 160 patients with acute heart failure and renal dysfunction into 2 groups (1:1). Loop diuretics doses were established according to CA125 levels in the CA125-guided group (n = 79) and in clinical evaluation in the usual-care group (n = 81). Changes in estimated glomerular filtration rate (eGFR) at 72 and 24 hours were the co-primary endpoints, respectively. Results: The mean age was 78 ± 8 years, the median amino-terminal pro-brain natriuretic peptide was 7765 pg/mL, and the mean eGFR was 33.7 ± 11.3 mL/min/1.73m2. Over 72 hours, the CA125-guided group received higher furosemide equivalent dose compared to usual care (P = 0.011), which translated into higher urine volume (P = 0.042). Moreover, patients in the active arm with CA125 >35 U/mL received the highest furosemide equivalent dose (P <0.001) and had higher diuresis (P = 0.013). At 72 hours, eGFR (mL/min/1.73m2) significantly improved in the CA125-guided group (37.5 vs 34.8, P = 0.036), with no significant changes at 24 hours (35.8 vs 39.5, P = 0.391). Conclusion: A CA125-guided diuretic strategy significantly improved eGFR and other renal function parameters at 72 hours in patients with acute heart failure and renal dysfunction

Spatiotemporally Controlled Cardiac Conduction Block Using High-Frequency Electrical Stimulation

Background: Methods for the electrical inhibition of cardiac excitation have long been sought to control excitability and conduction, but to date remain largely impractical. High-amplitude alternating current (AC) stimulation has been known to extend cardiac action potentials (APs), and has been recently exploited to terminate reentrant arrhythmias by producing reversible conduction blocks. Yet, low-amplitude currents at similar frequencies have been shown to entrain cardiac tissues by generation of repetitive APs, leading in some cases to ventricular fibrillation and hemodynamic collapse in vivo. Therefore, an inhibition method that does not lead to entrainment – irrespective of the stimulation amplitude (bound to fluctuate in an in vivo setting) – is highly desirable. Methodology/Principal Findings: We investigated the effects of broader amplitude and frequency ranges on the inhibitory effects of extracellular AC stimulation on HL-1 cardiomyocytes cultured on microelectrode arrays, using both sinusoidal and square waveforms. Our results indicate that, at sufficiently high frequencies, cardiac tissue exhibits a binary response to stimulus amplitude with either prolonged APs or no effect, thereby effectively avoiding the risks of entrainment by repetitive firing observed at lower frequencies. We further demonstrate the ability to precisely define reversible local conduction blocks in beating cultures without influencing the propagation activity in non-blocked areas. The conduction blocks were spatiotemporally controlled by electrode geometry and stimuli duration, respectively, and sustainable for long durations (300 s). Conclusion/Significance: Inhibition of cardiac excitation induced by high-frequency AC stimulation exhibits a binary response to amplitude above a threshold frequency, enabling the generation of reversible conduction blocks without the risks of entrainment. This inhibition method could yield novel approaches for arrhythmia modeling in vitro, as well as safer and more efficacious tools for in vivo cardiac mapping and radio-frequency ablation guidance applications

The intimate relationship between human cytomegalovirus and the dendritic cell lineage.

Primary infection of healthy individuals with human cytomegalovirus (HCMV) is normally asymptomatic but results in the establishment of a lifelong infection of the host. One important cellular reservoir of HCMV latency is the CD34+ haematopoietic progenitor cells resident in the bone marrow. Viral gene expression is highly restricted in these cells with an absence of viral progeny production. However, cellular differentiation into mature myeloid cells is concomitant with the induction of a full lytic transcription program, DNA replication and, ultimately, the production of infectious viral progeny. Such reactivation of HCMV is a major cause of morbidity and mortality in a number of immune-suppressed patient populations. Our current understanding of HCMV carriage and reactivation is that cellular differentiation of the CD34+ progenitor cells through the myeloid lineage, resulting in terminal differentiation to either a macrophage or dendritic cell (DC) phenotype, is crucial for the reactivation event. In this mini-review, we focus on the interaction of HCMV with DCs, with a particular emphasis on their role in reactivation, and discuss how the critical regulation of viral major immediate-early gene expression appears to be delicately entwined with the activation of cellular pathways in differentiating DCs. Furthermore, we also explore the possible immune consequences associated with reactivation in a professional antigen presenting cell and potential countermeasures HCMV employs to abrogate these

A three-dimensional human atrial model with fiber orientation. Electrograms and arrhythmic activation patterns relationship

The most common sustained cardiac arrhythmias in humans are atrial tachyarrhythmias, mainly atrial fibrillation. Areas of complex fractionated atrial electrograms and high dominant frequency have been proposed as critical regions for maintaining atrial fibrillation; however, there is a paucity of data on the relationship between the characteristics of electrograms and the propagation pattern underlying them. In this study, a realistic 3D computer model of the human atria has been developed to investigate this relationship. The model includes a realistic geometry with fiber orientation, anisotropic conductivity and electrophysiological heterogeneity. We simulated different tachyarrhythmic episodes applying both transient and continuous ectopic activity. Electrograms and their dominant frequency and organization index values were calculated over the entire atrial surface. Our simulations show electrograms with simple potentials, with little or no cycle length variations, narrow frequency peaks and high organization index values during stable and regular activity as the observed in atrial flutter, atrial tachycardia (except in areas of conduction block) and in areas closer to ectopic activity during focal atrial fibrillation. By contrast, cycle length variations and polymorphic electrograms with single, double and fragmented potentials were observed in areas of irregular and unstable activity during atrial fibrillation episodes. Our results also show: 1) electrograms with potentials without negative deflection related to spiral or curved wavefronts that pass over the recording point and move away, 2) potentials with a much greater proportion of positive deflection than negative in areas of wave collisions, 3) double potentials related with wave fragmentations or blocking lines and 4) fragmented electrograms associated with pivot points. Our model is the first human atrial model with realistic fiber orientation used to investigate the relationship between different atrial arrhythmic propagation patterns and the electrograms observed at more than 43000 points on the atrial surface.This work was partially supported by the Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica, Ministerio de Ciencia e Innovacion of Spain (TEC2008-02090), by the Plan Avanza (Accion Estrategica de Telecomunicaciones y Sociedad de la Informacion), Ministerio de Industria Turismo y Comercio of Spain (TSI-020100-2010-469), by the Programa Prometeo 2012 of the Generalitat Valenciana and by the Programa de Apoyo a la Investigacion y Desarrollo de la Universitat Politecnica de Valencia (PAID-06-11-2002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Tobón Zuluaga, C.; Ruiz Villa, CA.; Heidenreich, E.; Romero Pérez, L.; Hornero, F.; Saiz Rodríguez, FJ. (2013). A three-dimensional human atrial model with fiber orientation. Electrograms and arrhythmic activation patterns relationship. PLoS ONE. 8(2):1-13. https://doi.org/10.1371/journal.pone.0050883S11382Ho SY, Sanchez-Quintana D, Anderson RH (1998) Can anatomy define electric pathways? In: International Workshop on Computer Simulation and Experimental Assessment of Electrical Cardiac Function, Lausanne, Switzerland. 77–86.Tobón C (2009) Evaluación de factores que provocan fibrilación auricular y de su tratamiento mediante técnicas quirúrgicas. Estudio de simulación. Master Thesis Universitat Politècnica de València.Ruiz C (2010) Estudio de la vulnerabilidad a reentradas a través de modelos matemáticos y simulación de la aurícula humana. Doctoral Thesis Universitat Politècnica de València.Tobón C (2010) Modelización y evaluación de factores que favorecen las arritmias auriculares y su tratamiento mediante técnicas quirúrgicas. Estudio de simulación. Doctoral Thesis Universitat Politècnica de València.Henriquez, C. S., & Papazoglou, A. A. (1996). Using computer models to understand the roles of tissue structure and membrane dynamics in arrhythmogenesis. Proceedings of the IEEE, 84(3), 334-354. doi:10.1109/5.486738Grimm, R. A., Chandra, S., Klein, A. L., Stewart, W. J., Black, I. W., Kidwell, G. A., & Thomas, J. D. (1996). Characterization of left atrial appendage Doppler flow in atrial fibrillation and flutter by Fourier analysis. American Heart Journal, 132(2), 286-296. doi:10.1016/s0002-8703(96)90424-xMaleckar, M. M., Greenstein, J. L., Giles, W. R., & Trayanova, N. A. (2009). K+ current changes account for the rate dependence of the action potential in the human atrial myocyte. American Journal of Physiology-Heart and Circulatory Physiology, 297(4), H1398-H1410. doi:10.1152/ajpheart.00411.200