Modificaciones del automatismo, conducción, refractariedad miocárdicas y del patrón fibrilatorio ventricular producidas por el ejercicio físico crónico. Influencia del sistema nervioso cardiaco

El objetivo de este trabajo es investigar el papel de las neuronas parasimpáticas postganglionares en los cambios adaptativos producidos por el entrenamiento físico sobre el automatismo, la conducción y la refractariedad miocárdicas. Se utilizaron 41 conejos de raza New Zealand White que fueron divididos en 3 grupos: un grupo de animales control (n=14), un grupo de animales falsos operados (n=13) y un grupo de animals entrenados (n=14). Estos últimos fueron sometidos a un protocolo de entrenamiento en cinta rodante de 6 semanas de duración. El estudio electrofisiológico se realizó en corazón aislado y, por tanto, no sometido a influencias nerviosas extrínsecas ni humorales. Las propiedades electrofisiológicas investigadas en cada uno de los grupos fueron: (a) automatismo sinusal, (b) conducción auriculoventricular y ventriculoaricular, (c) refractariedad auricular, ventricular y del sistema de conducción y (d) la frecuencia dominante media de la fibrilación ventricular inducida. El protocolo electrofisiológico fue realizado antes y durante la infusión continua de atropina (1 μM), con el objetivo de bloquear los receptores muscarínicos cardíacos. El bloqueo colinérgico no modificó el incremento en la longitud de ciclo sinusal, la conducción auriculoventricular, la refractariedad (periodo refractario funcional tanto ventricular como del sistema de conducción auriculoventricular), ni el descenso en la frecuencia dominante de la fibrilación ventricular. De este modo, las modificaciones inducidas por el entrenamiento físico en corazón aislado de conejo no fueron revertidas por la administración de atropina. Estos resultados demuestran que, en nuestro modelo experimental, las modificaciones electrofisiológicas producidas por el entrenamiento físico no están mediadas por la actividad del sistema nervioso parasimpático intrínseco, por lo que es necesario seguir investigando los mecanismos básicos por los que se producen.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. We used 42 New Zealand Rabbits distributed in three groups: control group (n = 14), sham operated group (n = 13) and trained group (n = 14). Trained rabbits were submitted to a physical 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 different 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 fibrillation (VF), using a spectral method. The electrophysiological protocol was performed before and during continuous atropine administration (1μM), in order to block cholinergic receptors. Cholinergic receptor blockade did not modify the increase in sinus cycle length, atrioventricular conduction, refractoriness (left ventricular and atrioventricular conduction system functional refractory periods), and the decrease on DF of VF. Thus, the training-induced changes of the analyzed electrophysiological properties were not reverted by atropine administration. These findings reveal that, in our experimental model, the myocardial electrophysiological modications produced by physical training are not mediated by intrinsic parasympathetic activity. Further research is needed in order to elucidate the intrinsic modifications that are implied on those electrophysiological adaptations

Clasificación de registros de mapeado cardíaco en fibrilación ventricular

El presente trabajo estudia las modificaciones intrínsecas que el ejercicio físico produce en la respuesta cardíaca durante fibrilación ventricular (FV). Para ello se plantea el desarrollo de clasificadores (RL; regresión logística y ELM; Extreme Learning Machine) que diferencien entre el grupo control y los sujetos entrenados. Como parámetros de entrada a los clasificadores se han considerado dos relacionados con el espectro de la señal (FD: frecuencia dominante, y EN: energía normalizada), y otros relacionados con la regularidad y organización de las ondas de activación local, OAL, (IR: índice de regularidad y NO: número de ocurrencias). Se ha realizado un análisis de regiones de interés (ROI) de los tres primeros parámetros para valorar su uniformidad espacial. El trabajo tiene un doble objetivo: estudiar las capacidades de los distintos clasificadores y obtener información acerca de la importancia de las variables a la hora de realizar la clasificación. Se analizaron registros de mapeado cardíaco correspondientes a dos grupos: control (G1: sin entrenamiento, N=10) y entrenados (G2, N=9). Del estudio de las capacidades de ambos clasificadores, se puede observar cómo la ELM obtiene mejores índices de funcionamiento que la RL. Si se analiza el producto sensibilidad por especificidad en el conjunto de validación, se obtiene un 60.73% con la RL y un 72.37% con la ELM. En cuanto al análisis de variables, los resultados obtenidos sugieren que los cambios intrínsecos en FV debidos al ejercicio físico están relacionados con la regularidad morfológica y la uniformidad espectral de las señales de activación del tejido cardíaco

Optimizing beam-ion confinement in ITER by adjusting the toroidal phase of the 3D magnetic fields applied for ELM control

The confinement of neutral beam injection (NBI) particles in the presence of n = 3 resonant magnetic perturbations (RMPs) in 15 MA ITER DT plasmas has been studied using full orbit ASCOT simulations. Realistic NBI distribution functions, and 3D wall and equilibria, including the plasma response to the externally applied 3D fields calculated with MARS-F, have been employed. The observed total fast-ion losses depend on the poloidal spectra of the applied n = 3 RMP as well as on the absolute toroidal phase of the applied perturbation with respect to the NBI birth distribution. The absolute toroidal phase of the RMP perturbation does not affect the ELM control capabilities, which makes it a key parameter in the confinement optimization. The physics mechanisms underlying the observed fast-ion losses induced by the applied 3D fields have been studied in terms of the variation of the particle canonical angular momentum (δPϕ) induced by the applied 3D fields. The presented simulations indicate that the transport is located in an edge resonant transport layer as observed previously in ASDEX upgrade studies. Similarly, our results indicate that an overlapping of several linear and nonlinear resonances at the edge of the plasma might be responsible for the observed fast-ion losses. The results presented here may help to optimize the RMP configuration with respect to the NBI confinement in future ITER discharges.Spanish Ministry of Science, Innovation and Universities (grant BES2013-065501)EUROfusion Consortium grant agreement No. 633053European Union’s Horizon 2020 (grant agreement No. 805162)Academy of Finland project No. 32475

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. Am J Physiol Heart Circ Physiol 281:1346–1352Inoue H, Zipes DP (1987) Changes in atrial and ventricular refractoriness and atrioventricular nodal conduction produced by combinations of vagal and sympathetic stimulation that result in a constant spontaneous sinus cycle length. Circ Res 60:942–951Jew KN, Olsson MC, Mokelke EA, Palmer BM, Moore RL (2001) Endurance training alters outward K+ current characteristics in rat cardiocytes. J Appl Physiol 90:1327–1333Johnson TA, Gray AL, Lauenstein JM, Newton SS, Massari VJ (2004) Parasympathetic control of the heart I. An interventriculo-septal ganglion is the major source of the vagal intracardiac innervation of the ventricles. J Appl Physiol 96:2265–2272. doi: 10.1152/japplphysiol.00620.2003Katona PG, McLean M, Dighton DH, Guz A (1982) Sympathetic and parasympathetic cardiac control in athletes and nonathletes at rest. J Appl Physiol 52:1652–1657Lewis SF, Nylander E, Gad P, Areskog N (1980) Non-autonomic component in bradycardia of endurance trained men at rest and during exercise. Acta Physiol Scand 109:297–305Litovsky SH, Antzelevitch C (1990) Differences in the electrophysiological response of canine ventricular subendocardium and subepicardium to acetylcholine and isoproterenol. A direct effect of acetylcholine in ventricular myocardium. Circ Res 67:615–627Löffelholz K (1981) Release of acetylcholine in the isolated heart. Am J Physiol 240(4):H431–H440Lopatin AN, Nichols CG (2001) Inward rectifiers in the heart: an update on I(K1). J Mol Cell Cardiol 33:625–638. doi: 10.1006/jmcc.2001.1344Mace LC, Palmer BM, Brown DA, Jew KN, Lynch JM, Glunt JM, Parsons TA, Cheung JY, Moore RL (2003) Influence of age and run training on cardiac Na+/Ca2+ exchange. J Appl Physiol 95:1994–2003. doi: 10.1152/japplphysiol.00551.2003Martins JB, Zipes DP (1980) Effects of sympathetic and vagal nerves on recovery properties of the endocardium and epicardium of the canine left ventricle. Circ Res 46:100–110Mezzani A, Giovannini T, Michelucci A, Padeletti L, Resina A, Cupelli V, Musante R (1990) Effects of training on the electrophysiologic properties of atrium and accessory pathway in athletes with Wolff–Parkinson–White syndrome. Cardiology 77:295–302Mokelke EA, Palmer BM, Cheung JY, Moore RL (1997) Endurance training does not affect intrinsic calcium current characteristics in rat myocardium. Am J Physiol Heart Circ Physiol 273:H1193–H1197Mont L, Elosua R, Brugada J (2009) Endurance sport practice as a risk factor for atrial fibrillation and atrial flutter. Europace 11:11–17. doi: 10.1093/europace/eun289Moore RL, Korzick DH (1995) Cellular adaptations of the myocardium to chronic exercise. Prog Cardiovasc Dis 37:371–396Negrao CE, Moreira ED, Santos MC, Farah VM, Krieger EM (1992) Vagal function impairment after exercise training. J Appl Physiol 72:1749–1753Ng GA, Brack KE, Coote JH (2001) Effects of direct sympathetic and vagus nerve stimulation on the physiology of the whole heart—a novel model of isolated Langendorff perfused rabbit heart with intact dual autonomic innervation. Exp Physiol 86:319–329Nylander E, Sigvardsson K, Kilbom A (1982) Training-induced bradycardia and intrinsic heart rate in rats. Eur J Appl Physiol Occup Physiol 48:189–199Panfilov AV (2006) Is heart size a factor in ventricular fibrillation? Or how close are rabbit and human hearts? Heart Rhythm 3:862–864. doi: 10.1016/j.hrthm.2005.12.022Papka RE (1976) Studies of cardiac ganglia in pre- and postnatal rabbits. Cell Tissue Res 175:17–35Pardini BJ, Patel KP, Schmid PG, Lund DD (1987) Location, distribution and projections of intracardiac ganglion cells in the rat. J Auton Nerv Syst 20:91–101Scott AS, Eberhard A, Ofir D, Benchetrit G, Dinh TP, Calabrese P, Lesiuk V, Perrault H (2004) Enhanced cardiac vagal efferent activity does not explain training-induced bradycardia. Auton Neurosci 112:60–68. doi: 10.1016/j.autneu.2004.04.006Seals DR, Chase PB (1989) Influence of physical training on HR variability and baroreflex circulatory control. J Appl Physiol 66:1886–1895Shi X, Stevens GHJ, Foresman BH, Stern SA, Raven PB (1995) Autonomic nervous system control of the heart: endurance exercise training. Med Sci Sports Exerc 27:1406–1413Snyders DJ (1999) Structure and function of cardiac potassium channels. Cardiovasc Res 42:377–390Stein R, Moraes RS, Cavalcanti AV, Ferlin EL, Zimerman LI, Ribeiro JP (2000) Atrial automaticity and atrioventricular conduction in athletes: contribution of autonomic regulation. Eur J Appl Physiol 82:155–157Stein R, Moraes RS, Cavalcanti AV, Ferlin EL, Zimerman LI, Ribeiro JP (2002) Intrinsic sinus and atrioventricular node electrophysiologic adaptations in endurance athletes. J Am Coll Cardiol 39:1033–1038Stones R, Billeter R, Zhang H, Harrison S, White E (2009) The role of transient outward K+ current in electrical remodelling induced by voluntary exercise in female rat hearts. Basic Res Cardiol 104:643–652. doi: 10.1007/s00395-009-0030-6Such L, Rodríguez A, Alberola A, López L, Ruiz R, Artal L, Pons I, Pons ML, García C, Chorro FJ (2002) Intrinsic changes on automatism, conduction and refractoriness by exercise in insolated rabbit heart. J Appl Physiol 92:225–229. doi: 10.1111/j.1748-1716.2008.01851.xSuch L, Alberola AM, Such-Miquel L, López L, Trapero I, Pelechano F, Gómez-Cabrera MC, Tormos A, Millet J, Chorro FJ (2008) Effects of chronic exercise on myocardial refractoriness: a study on isolated rabbit heart. Acta Physiol 193:331–339Vigmond EJ, Tsoi V, Kuo S, Arevalo H, Kneller J, Nattel S, Trayanova N (2004) The effect of vagally induced dispersion of action potential duration on atrial arrhythmogenesis. Heart Rhythm 1:334–344. doi: 10.1016/j.hrthm.2004.03.077Zipes DP, Mihalick MJ, Robbins GT (1974) Effects of selective vagal and stellate ganglion stimulation of atrial refractoriness. Cardiovasc Res 8:647–65

Beam-ion transport dependence on Magnetic Perturbations spectrum and plasma helicity in the ASDEX Upgrade tokamak

EUROfusion Consortium 63305

Characterisation of the fast-ion edge resonant transport layer induced by 3D perturbative fields in the ASDEX Upgrade tokamak through full orbit simulations

In recent experiments at the ASDEX Upgrade tokamak the existence of an Edge Resonant Transport Layer (ERTL) was revealed as the main transport mechanism responsible for the measured fast-ion losses in the presence of externally applied 3D fields. The Monte Carlo orbit-following code ASCOT was used to study the fast-ion transport including the plasma response calculated with MARS-F, reproducing a strong correlation of fast-ion losses with the poloidal mode spectra of the 3D fields. In this work, a description of the physics underlying the ERTL is presented by means of numerical simulations together with an analytical model and experimental measurements to validate the results. The degradation of fast-ion confinement is calculated in terms of the variation of the toroidal canonical momentum (δPϕ). This analysis reveals resonant patterns at the plasma edge activated by 3D perturbations and emphasizes the relevance of nonlinear resonances. The impact of collisions and the radial electric field on the ERTL is analysed.EUROfusion Consortium 633053French National Research Agency (ANR) ANR-11-IDEX-0001-0

PPARγ as an indicator of vascular function in an experimental model of metabolic syndrome in rabbits

Background and aims: Underlying mechanisms associated with vascular dysfunction in metabolic syndrome (MetS) remain unclear and can even vary from one vascular bed to another. Methods: In this study, MetS was induced by a high-fat, high-sucrose diet, and after 28 weeks, aorta and renal arteries were removed and used for isometric recording of tension in organ baths, protein expression by Western blot, and histological analysis to assess the presence of atherosclerosis. Results: MetS induced a mild hypertension, pre-diabetes, central obesity and dyslipidaemia. Our results indicated that MetS did not change the contractile response in either the aorta or renal artery. Conversely, vasodilation was affected in both arteries in a different way. The aorta from MetS showed vascular dysfunction, including lower response to acetylcholine and sodium nitroprusside, while the renal artery from MetS presented a preserved relaxation to acetylcholine and an increased sensitivity to sodium nitroprusside. We did not find vascular oxidative stress in the aorta from MetS, but we found a significant decrease in PPARγ, phospho-Akt (p-Akt) and phospho-eNOS (p-eNOS) protein expression. On the other hand, we found oxidative stress in the renal artery from MetS, and PPARγ, Akt and p-Akt were overexpressed. No evidence of atherosclerosis was found in arteries from MetS. Conclusions: MetS affects vascular function differently depending on the vessel. In the aorta, it decreases both the vasodilation and the expression of the PPARγ/Akt/eNOS pathway, while in the renal artery, it increases the expression of PPARγ/Akt signalling pathway without decreasing the vasodilation

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. PLoS ONE. 13(12). https://doi.org/10.1371/journal.pone.0209085S1312Billman, G. E. (2002). Aerobic exercise conditioning: a nonpharmacological antiarrhythmic intervention. Journal of Applied Physiology, 92(2), 446-454. doi:10.1152/japplphysiol.00874.2001Billman, G. E. (2006). A comprehensive review and analysis of 25 years of data from an in vivo canine model of sudden cardiac death: Implications for future anti-arrhythmic drug development. Pharmacology & Therapeutics, 111(3), 808-835. doi:10.1016/j.pharmthera.2006.01.002Dor-Haim, H., Berenfeld, O., Horowitz, M., Lotan, C., & Swissa, M. (2013). Reduced Ventricular Arrhythmogeneity and Increased Electrical Complexity in Normal Exercised Rats. PLoS ONE, 8(6), e66658. doi:10.1371/journal.pone.0066658Hamer, M., & Stamatakis, E. (2008). Physical Activity and Cardiovascular Disease: Directions for Future Research. The Open Sports Sciences Journal, 1(1), 1-2. doi:10.2174/1875399x00801010001Powers, S. K., Smuder, A. J., Kavazis, A. N., & Quindry, J. C. (2014). Mechanisms of Exercise-Induced Cardioprotection. Physiology, 29(1), 27-38. doi:10.1152/physiol.00030.2013Hull, S. S., Vanoli, E., Adamson, P. B., Verrier, R. L., Foreman, R. D., & Schwartz, P. J. (1994). Exercise training confers anticipatory protection from sudden death during acute myocardial ischemia. Circulation, 89(2), 548-552. doi:10.1161/01.cir.89.2.548Hajnal, Á., Nagy, O., Litvai, Á., Papp, J., Parratt, J. R., & Végh, Á. (2005). Nitric oxide involvement in the delayed antiarrhythmic effect of treadmill exercise in dogs. Life Sciences, 77(16), 1960-1971. doi:10.1016/j.lfs.2005.02.015Such, L., Alberola, A. M., Such-Miquel, L., López, L., Trapero, I., Pelechano, F., … Chorro, F. J. (2008). Effects of chronic exercise on myocardial refractoriness: a study on isolated rabbit heart. Acta Physiologica, 193(4), 331-339. doi:10.1111/j.1748-1716.2008.01851.xZarzoso, M., Such-Miquel, L., Parra, G., Brines-Ferrando, L., Such, L., Chorro, F. J., … Alberola, A. (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). Intrinsic changes on automatism, conduction, and refractoriness by exercise in isolated rabbit heart. Journal of Applied Physiology, 92(1), 225-229. doi:10.1152/jappl.2002.92.1.225Duytschaever, M., Mast, F., Killian, M., Blaauw, Y., Wijffels, M., & Allessie, M. (2001). Methods for Determining the Refractory Period and Excitable Gap During Persistent Atrial Fibrillation in the Goat. Circulation, 104(8), 957-962. doi:10.1161/hc3401.093156Wijffels, M. C. E. F., Kirchhof, C. J. H. J., Dorland, R., & Allessie, M. A. (1995). Atrial Fibrillation Begets Atrial Fibrillation. Circulation, 92(7), 1954-1968. doi:10.1161/01.cir.92.7.1954Zaitsev, A. V., Berenfeld, O., Mironov, S. F., Jalife, J., & Pertsov, A. M. (2000). Distribution of Excitation Frequencies on the Epicardial and Endocardial Surfaces of Fibrillating Ventricular Wall of the Sheep Heart. Circulation Research, 86(4), 408-417. doi:10.1161/01.res.86.4.408Armour, J. A., Collier, K., Kember, G., & Ardell, J. L. (1998). Differential selectivity of cardiac neurons in separate intrathoracic autonomic ganglia. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 274(4), R939-R949. doi:10.1152/ajpregu.1998.274.4.r939Armour, J. A., & Hopkins, D. A. (1990). Activity of in vivo canine ventricular neurons. American Journal of Physiology-Heart and Circulatory Physiology, 258(2), H326-H336. doi:10.1152/ajpheart.1990.258.2.h326D’Souza, A., Bucchi, A., Johnsen, A. B., Logantha, S. J. R. J., Monfredi, O., Yanni, J., … Boyett, M. R. (2014). Exercise training reduces resting heart rate via downregulation of the funny channel HCN4. Nature Communications, 5(1). doi:10.1038/ncomms4775Sartiani, L., Romanelli, M., Mugelli, A., & Cerbai, E. (2015). Updates on HCN Channels in the Heart: Function, Dysfunction and Pharmacology. Current Drug Targets, 16(8), 868-876. doi:10.2174/1389450116666150531152047Herrmann, S., Layh, B., & Ludwig, A. (2011). Novel insights into the distribution of cardiac HCN channels: An expression study in the mouse heart. Journal of Molecular and Cellular Cardiology, 51(6), 997-1006. doi:10.1016/j.yjmcc.2011.09.005Welch, P. (1967). The use of fast Fourier transform for the estimation of power spectra: A method based on time averaging over short, modified periodograms. IEEE Transactions on Audio and Electroacoustics, 15(2), 70-73. doi:10.1109/tau.1967.116190

Exercise Training Protocols in Rabbits Applied in Cardiovascular Research

Rabbit exercise protocols allow for the evaluation of physiological and biomechanical changes and responses to episodes of acute or chronic exercise. The observed physiological changes are normal responses to stress, that is, adaptive responses to maintain or restore homeostasis after acute exercise. Indeed, the rabbit model is advantageous since (a) it has important physiological similarities in terms of the functioning of multiple organ systems, and can quickly induce alterations in pathophysiological conditions that resemble those of humans, and (b) it allows the implementation of a low-cost model in comparison with other large animals. When designing an exercise training protocol for rabbits, it is important to consider variables such as race, gender, age and, especially, training parameters such as volume, intensity, or rest, among others, to determine the outcome of the research. Therefore, the objective of this review is to identify and analyze exercise training protocols in rabbits in different experimental applications and the various physiological adaptations that are presented, with special focus in cardiovascular adaptations

Diet-Induced Rabbit Models for the Study of Metabolic Syndrome

Obesity and metabolic syndrome (MetS) have become a growing problem for public health and clinical practice, given their increased prevalence due to the rise of sedentary lifestyles and excessive caloric intake from processed food rich in fat and sugar. There are several definitions of MetS, but most of them describe it as a cluster of cardiovascular and metabolic alterations such as abdominal obesity, reduced high-density lipoprotein (HDL) and elevated low-density lipoprotein (LDL) cholesterol, elevated triglycerides, glucose intolerance, and hypertension. Diagnosis requires three out of these five criteria to be present. Despite the increasing prevalence of MetS, the understanding of its pathophysiology and relationship with disease is still limited. Indeed, the pathological consequences of MetS components have been reported individually, but investigations that have studied the effect of the combination of MeS components on organ pathological remodeling are almost nonexistent. On the other hand, animal models are a powerful tool in understanding the mechanisms that underlie pathological processes such as MetS. In the first part of the review, we will briefly overview the advantages, disadvantages and pathological manifestations of MetS in porcine, canine, rodent, and rabbit diet-induced experimental models. Then, we will focus on the different dietary regimes that have been used in rabbits to induce MetS by means of high-fat, cholesterol, sucrose or fructose-enriched diets and their effects on physiological systems and organ remodeling. Finally, we will discuss the use of dietary regimes in different transgenic strains and special rabbit breeds