Papers by Julio Gomis-Tena Dolz
La corriente de cloro dependiente de calcio (I Cl,Ca) es una de las corrientes que atraviesan la ... more La corriente de cloro dependiente de calcio (I Cl,Ca) es una de las corrientes que atraviesan la membrana celular presente en numerosas especies animales. Ha sido objeto de atencion durante la ultima decada y numerosos trabajos cientificos han caracterizado su comportamiento. Actua como la componente segunda de una corriente transitoria de salida durante la fase 1 del potencial de accion y, a diferencia de la componente primera, no se atenua al incrementarse la frecuencia de estimulacion. Durante la fase de reposo es una de las componentes de una corriente transitoria de entrada que provoca la aparicion de postdespolarizaciones tardias (DAD) cuya propagacion da lugar a arritmias por actividad inducida. Hata el momento no se ha formulado un modelo matematico que describa el comportamiento de la corriente de cloro. Es objetivo de la presente Tesis Doctoral desarrollar dicho modelo matematico e introducirlo en un modelo de potencial de accion de celulas cardiacas de auricula de conejo. Esto permitira esclarecer algunos de los mecanismos ionicos involucrados en la actividad electrica celular en condiciones de normalidad fisiologica y en condiciones patologicas inductoras de arritmias. Para abordar el estudio de la propagacion se han empleado modelos unidimensionales multicelulares que reproducen la actividad de las fibras cardiacas. Los resultados muestran que, en condiciones normales, la corriente contribuye a mantener la duracion del potencial de accion estable ante incrementos en la frecuencia de estimulacion; que en condiciones en las que se favorece la aparicion de DAD su bloqueo tiene efectos antiarritmicos al reducirse la amplitud de la DAD y que, en situaciones que ayudan a la generacion de postdespolarizaciones tempranas (EAD), el bloqueo de la corriente tiene efectos proarritmicos.
Computer Methods and Programs in Biomedicine
Animal - science proceedings
European Heart Journal, 2020
Introduction It is well recognized that early identification of drug-induced proarrhythmic safety... more Introduction It is well recognized that early identification of drug-induced proarrhythmic safety risks is crucial to drug development for ethical, animal sparing and costs reduction considerations. The availability, however, of easily accessible, user-friendly tools for real time assessments of the proarrhythmic potential of chemical compounds has been lacking. The novel Tx index, implemented in the presented web-based tool, was applied to a dataset of 84 compounds. Materials and methods The tool is based on 206,766 cellular simulations of compound-induced effects on Action Potential Duration (APD) in isolated endocardial, midmyocardial, and epicardial cells and on 7,072 tissue simulations on QT prolongation in a virtual tissue. Simulations were performed by blocking the slow and the fast components of the delayed rectifier current (IKs and IKr, respectively) and the L-type calcium current (ICaL) at different levels. Based on these simulations, four Tx indices were defined as the r...
Computers in Cardiology, 2003, 2003
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Atrial action potential (AP) alte... more Atrial fibrillation (AF) is the most common cardiac arrhythmia. Atrial action potential (AP) alternans appearance during atrial flutter play a determinant role as AF precursor. AP alternans involves intracellular calcium concentration alternation that affects calcium dependent currents like I NaCa and I ClCa. In this study, a modified rabbit atrial AP mode, that includes I Cl,Ca formulation is used. In order to induce alternans, the pacing cycle length was abruptly shortened from a basic drive of 1000 ms after 7.5 s of stimulation. The role of I ClCa was investigated by blocking the current. When increasing pace rate, from a cycle length of 1000 ms to 180 ms, beat-to-beat alternans appear. Repeating the procedure in I ClCa blockade situation, in the range of 60 to 100 %, alternans dessapear. Our results suggest that I ClCa blockade prevents alternans and for this reason I ClCa blockade could be potentially antiarrhythmic, preventing AF.
Proceedings of the 25th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (IEEE Cat. No.03CH37439)
ABSTRACT Atrial fibrillation (AF) is a common cardiac arrhythmia. The appearance of alternans of ... more ABSTRACT Atrial fibrillation (AF) is a common cardiac arrhythmia. The appearance of alternans of atrial action potential (AP) during atrial flutter could play a determinant role as a precursor of AF. The ionic basis for these beat-to-beat changes in AP involves intracellular calcium cycling in the maintenance of alternans. Alterations of intracellular calcium concentration affect to calcium dependent currents like INaCa and ICl,Ca. In this study, a modified rabbit atrial AP model, that includes ICl,Ca formulation, is used. Alternans generation was induced by increasing pace rate (from a cycle length of 1000 to 180 ms). In this situation, our results show that ICl,Ca blockade (60% of nominal) inhibits alternans. It suggests that ICl,Ca blockade could play an important antiarrhythmogenic role.
Journal of Dairy Science, 2020
The objective of this experiment was to study the effects of incorporating lemon leaves and rice ... more The objective of this experiment was to study the effects of incorporating lemon leaves and rice straw into the compound feed of diets for dairy goats. Ten Murciano-Granadina dairy goats (n = 5 per group) in mid-lactation were used in a crossover design experiment (2 treatments across 2 periods). Goats were fed a mixed ration with barley grain (control, CON) or CON plus lemon leaves [189 g/kg of dry matter (DM)] and rice straw (120 g/kg of DM) in place of barley grain (LRS). Soybean oil (19 g/kg of DM) was added to the LRS diet to make it isoenergetic (17 MJ of gross energy/kg of DM) relative to CON. After 14 d on their respective treatments, goats were allocated to individual metabolism cages for another 7 d. Subsequently, feed intake, total fecal and urine output, and milk yield were recorded daily over the first 5 d. During the last 2 d, ruminal fluid and blood samples were collected, along with individual gas exchange measurements recorded by a mobile open-circuit indirect calorimetry system using a head box. No differences in DM intake were detected, and ME intake in LRS was lower than in CON (1,095 vs. 1,180 kJ/kg of metabolic body weight). No differences were observed in milk production, but milk fat content was greater in LRS (6.4%) than in CON (5.6%). Greater concentrations of monounsaturated (14.94 vs. 11.96 g/100 g of milk fat) and polyunsaturated fatty acids (4.53 vs. 4.03 g/100 g of milk fat) were detected in the milk of goats fed LRS compared with CON. Atherogenicity (2.68 vs.1.91) and thrombogenic (4.58 vs. 2.81) indices were lower with LRS compared with CON. Enteric CH 4 emission was lower in LRS (24.3 g/d) compared with CON (31.1 g/d), probably due to the greater lipid content and unsaturated fatty acid profile of lemon leaves and the soybean oil added in the LRS diet. Overall, data suggest that incorporating lemon leaves and rice straw into lactating goat diets is effective in reducing CH 4 emissions while allowing improvements in milk fat production and milk thrombogenic index without affecting production performance. Thus, their inclusion in compound feeds fed to small ruminants appears warranted and would have multiple positive effects, as on efficiency of nutrient use, human health, and the environment.
Computers in Cardiology 1999. Vol.26 (Cat. No.99CH37004)
Shows a new mathematical model for the cardiac Ca-dependent chloride current (ICl,Ca). This model... more Shows a new mathematical model for the cardiac Ca-dependent chloride current (ICl,Ca). This model has been introduced in the Lindblad et al. (1996) model of rabbit atrial cell (LMCG model), and it is used to test the role of this current in normal and pathological situations. For normal situations, ICl,Ca is the second component of a transient outward current (Ito)
The aim is to study the influence of transient chloride calcium-dependent outward current (ClCa) ... more The aim is to study the influence of transient chloride calcium-dependent outward current (ClCa) on cardiac action potential (AP) at the pathological conditions that induces early after depolarizations (EAD). A detailed mathematical model of this current was introduced into Lindblad-Murphey-Clark-Giles model of cardiac action potential, and the electrical activity in a cell was simulated for various conditions. Our results show that ClCa current must be take into account as important mechanism to avoid EADs generation
High intracellular calcium concentration causes a transient inward current (I/sub n/) that can pr... more High intracellular calcium concentration causes a transient inward current (I/sub n/) that can provoke delayed after-depolarizations (DAD). I/sub n/ is comprised of sodium-calcium exchange current (I/sub NaCa/) and calcium-activated chloride current (I/sub ClCa/). We have developed a mathematical model of I/sub ClCa/ that was included into the atrium AP model by Linblad, Murphey, Clark and Giles (1996) (LMCG model). I/sub ClCa/ appears as an important component (30-40%) of I/sub n/. The plots of DAD amplitudes and DAD higher slope as a function of extracellular Ca/sup 2+/ concentration show an interval between 5 mM/l to 6 mM/l in which I/sub ClCa/ blockade could bring the DAD amplitude to a subthreshold level for triggered action potentials. Our results suggest that, at a high intracellular Ca/sup 2+/ concentration, that provokes DAD generating conditions, I/sub ClCa/ blockade could be potentially antiarrythmogenic.
Computers in Cardiology, 2004, 2004
Different experimental studies have shown that ventricular cells present several differences betw... more Different experimental studies have shown that ventricular cells present several differences between epicardium, endocardium and M-cells. M-cells have longer APDs and higher sensitivity to agents with class III actions and they could contribute to APD heterogeneity in the ventriculum. However, in-vivo studies have observed that the strong cellular coupling reduces the APD dispersion in intact heart. We used the Luo and Rudy model (LRd00) of AP and the model of IKr blockade by the action of dofetilide developed previously by our group to study the effect of dofetilide (a class III antiarrhythmic drug) on the APD dispersion in a strand of ventricular tissue. Our results show that dofetilide increases dramatically the APD dispersion and may modify the transmural gradient of APD even in normal coupling conditions such as those in intact heart. Higher dispersion and, a more complex behaviour, such as 2:1 block, could appear when the coupling decreases.
Computers in Cardiology, 2005, 2005
A computer model has been developed in which reflection was observed. Reflection is a type of ree... more A computer model has been developed in which reflection was observed. Reflection is a type of reentry in a one-dimensional structure of cardiac cells. The model consists of two segments of ventricular tissue partially coupled by a coupling resistance (R) and it was used to study conditions that provoke the development of EADs, and the generation of reflection and ectopic activity. In the present study, EADs were induced in one segment by enhancing I CaL current and decreasing I Kr and I Ks currents. The other segment was maintained under normal physiological conditions. The results suggest that ectopic activity in a zone of myocardium could appear due to the reflection induced by EADs generated in neighboring tissue zones. The coupling between areas and the blocked factor of the two components of the delayed rectifier K + current (I Kr and I Ks), have a great influence. The results suggest that a partial coupling between segments and severe conditions in the abnormal segment increase the likelihood of both the ectopic activity and the triggered activity.
Computers in Cardiology, 2003, 2003
Dofetilide selectively inhibits the rapid component of the delayed potassium current (I Kr). In t... more Dofetilide selectively inhibits the rapid component of the delayed potassium current (I Kr). In this work, a mathematical model of dofetilide effects on I Kr has been developed. This model has been incorporated to the Luo and Rudy (II) model of guinea pig ventricular action potential and the effect of different dofetilide concentrations on the action potential characteristics has been studied. Our results show that the steady-state block of I Kr is dose-dependent with a block of 10%, 53% and 92% for 1 nM, 10 nM and 100 nM of dofetilide respectively (IC 50 = 8.7 nM). This increment of I Kr block when the concentration increases induces a prolongation of APD also in a dose-dependent way. We observed prolongations of APD 90 of 13% and 28% for 10 nM and 100 nM of d ofetilide respectively. In agreement with experimental results, the interaction between dofetilide and the receptor in the channel presents slow kinetics and reverse use-dependence in our model.
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2010
The aim of this study was to investigate sex and age related differences in drug induced QT prolo... more The aim of this study was to investigate sex and age related differences in drug induced QT prolongation by dofetilide under reduced repolarization reserve in simulated ventricular cells. Left ventricular endocardial action potentials were simulated using a modified Luo Rudy model. Sex, age and regional differences in currents I(CaL), IK(r), IK(s), and I(to) were incorporated into the model by modifying the equations representing them. A model of dofetilide, a class III antiarrhythmic drug, was developed and included into a ventricular cell models. The reduced repolarization reserve was reproduced decreasing the IKs current. Our results shown that the adult female cells had longer action potentials, a steeper APD-BCL relationship and a higher susceptibility to EADs than adult male cells, under control, drug induced and reduced repolarization reserve conditions. On the other hand, young female and young male cells had similar action potentials under control conditions. However, young...
IEEE Transactions on Biomedical Engineering, 2011
Dofetilide is a class-III drug that inhibits the rapid component of the delayed potassium current... more Dofetilide is a class-III drug that inhibits the rapid component of the delayed potassium current ( I(Kr)). Experimental studies have shown that the different layers of ventricular muscle present differences in action potential duration (APD) and different responses to class III agents. It has been suggested that it contributes to APD heterogeneity in the ventricles. However, in vivo studies suggest that the strong cellular coupling reduces APD dispersion in intact heart. The aim of this paper is to study the effect of dofetilide on the action potentials (APs) in isolated ventricular cells and on APD dispersion in a strand of ventricular tissue. A mathematical model of dofetilide effects on I(Kr) has been developed and incorporated into the Luo--Rudy dynamic model of ventricular AP. Our results show that dofetilide induces in midmyocardium cells a faster time-course inhibition of I(Kr) than in endocardial or epicardial cells, and periods of instability with beat-to-beat APs variability. This behavior could favor temporal dispersion of repolarization between the different cells. The results also indicate that although dofetilide increases, the transmural gradient of APD in the ventricular wall, early afterdepolarizations (EADs) did not appear even under strong uncoupling conditions. However, reduced repolarization reserve favors the induction of EADs, even under normal coupling conditions.
The aim of this study was to investigate interactions between acquired long QT syndrome by dofeti... more The aim of this study was to investigate interactions between acquired long QT syndrome by dofetilide and reduced repolarization reserve in simulated human ventricular cells using prolongation of APD and triangulation of action potential. A Markovian model of hERG capable of reproducing a wild type as well an acquired long QT syndrome by dofetilide was developed and was included into a ventricular cell model for action potential simulation. Dofetilide concentrations used were 7.5, 30 and 100 nM. The endocardial and midmyocardial cells were paced with different basic cycle lengths (750, 1000 and 1250 ms). The reduced repolarization reserve was reproduced decreasing the IKs current by 50 and 25%. The results pointed out that triangulation offers an additional more sensitive and accurate indicator of the proarrhythmic potential of a drug than APD prolongation alone.
The aim of this study was to investigate the risk of proarrhythmia by dofetilide in gender and ag... more The aim of this study was to investigate the risk of proarrhythmia by dofetilide in gender and age based differences using action potential duration and triangulation of action potential. Left ventricular epicardial, midmyocardial and endocardial action potentials were simulated using a modified Luo Rudy model. Sex, age and regional differences in current densities and voltage dependent parameters for I CaL , IK r , IK s , and I to were incorporated into the model by modifying the equations representing them. A model of dofetilide was developed and included into a ventricular cell model. This study has demonstrated that gender and age based differences in ionic currents and drug induced action of dofetilide might explain in part the higher susceptibility of EADs and prevalence of TdP in adult females and the higher risk of cardiac events in males than females during childhood.
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Papers by Julio Gomis-Tena Dolz