A. Loewe, Y. Lutz, M. Wilhelms, D. Sinnecker, P. Barthel, E. P. Scholz, O. Dössel, G. Schmidt, and G. Seemann. In-silico assessment of the dynamic effects of amiodarone and dronedarone on human atrial patho-electrophysiology.. In Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, vol. 16(S4) , pp. iv30-iv38, 2014
AIMS: The clinical efficacy in preventing the recurrence of atrial fibrillation (AF) is higher for amiodarone than for dronedarone. Moreover, pharmacotherapy with these drugs is less successful in patients with remodelled substrate induced by chronic AF (cAF) and patients suffering from familial AF. To date, the reasons for these phenomena are only incompletely understood. We analyse the effects of the drugs in a computational model of atrial electrophysiology. METHODS AND RESULTS: The Courtemanche-Ramirez-Nattel model was adapted to represent cAF remodelled tissue and hERG mutations N588K and L532P. The pharmacodynamics of amiodarone and dronedarone were investigated with respect to their dose and heart rate dependence by evaluating 10 descriptors of action potential morphology and conduction properties. An arrhythmia score was computed based on a subset of these biomarkers and analysed regarding circadian variation of drug concentration and heart rate. Action potential alternans at high frequencies was observed over the whole dronedarone concentration range at high frequencies, while amiodarone caused alternans only in a narrow range. The total score of dronedarone reached critical values in most of the investigated dynamic scenarios, while amiodarone caused only minor score oscillations. Compared with the other substrates, cAF showed significantly different characteristics resulting in a lower amiodarone but higher dronedarone concentration yielding the lowest score. CONCLUSION: Significant differences exist in the frequency and concentration-dependent effects between amiodarone and dronedarone and between different atrial substrates. Our results provide possible explanations for the superior efficacy of amiodarone and may aid in the design of substrate-specific pharmacotherapy for AF.
Chronic kidney disease (CKD) affects more than 30 million patients in the European Union. CKD causes alterations in the extracellular plasma electrolyte concentrations, which affect cardiac electrophysiology. A total of 25% of all deaths of CKD patients are due to sudden cardiac death (SCD). Until recently, ventricular fibrillation was assumed to be the main reason. In a 2015 study, Wong et al. observed bradycardia and asystole as the predominant mechanisms of SCD in patients with CKD. This shows that the influence of electrolyte changes on the underlying mechanisms of pacemaking in the sinoatrial node (SAN) needs to be better understood. In this work, we have updated the computational model of the human SAN given by Fabbri et al. and investigated the CKD-induced change of [Ca2+]o (0.6-3mM), [K+]o (3-9mM) and [Na+]o (120-150mM) on pacemaking. [Ca2+]o had the most dominant effects on SAN function. Low [Ca2+]o caused severe bradycardia in the model (down to 17 bpm) for 0.6 mM. A critical concentration range of calcium in the subspace [Ca2+]sub was identified as the possible underlying mechanism for pacemaking. For increasing [Ca2+]o, the heart rate (HR) increased, resulting in 142 bpm for the highest calcium concentration. The effect of [K+]o variation was similar to the one for [Ca2+]o, but caused less pronounced change. The resultant changes due to variation of [Na+]o were relatively small. In this work, several potential mechanisms for SCD in CKD patients could be identified. The low HR for low [Ca2+]o is seen as a possible link to the observed bradycardia in CKD patients. The findings in this work could lead to a better surveillance of [Ca2+]o in hemodialysis patients, and therefore to a decrease in the SCD rate.
Y. Lutz, A. Loewe, O. Dössel, and G. Seemann. Specific antiarrhythmic therapy for familial atrial fibrillation in a numerical model of human atrial electrophysiology. In Biomedizinische Technik / Biomedical Engineering, vol. 59(s1) , pp. s933-s936, 2014
Atrial fibrillation (AF) is still a major health problem in the western society. Especially for familial AF, the pharmacological therapy is still not sufficiently successful. In this work, channel blocker properties were in-silico adapted to optimize drug therapy for patients suffering from familial AF. The Courtemanche-Ramirez-Nattel (CRN) cell model was the basis for the simulations. Adaptations in the model due to familial AF were implemented using an existing description of the L532P mutation. A fitting algorithm was designed which adapted all conductivities of the ion channels described in the CRN model to restore the healthy action potential (AP). To find the minimal deviation of the healthy AP and the AP of the L532P mutation, the trust-region-reflective algorithm was used. The best matched APs were achieved by a significant blockade of the IKr and the IKur current. 1D tissue strand simulations were performed using different basic cycle lengths (BCL) to evaluate the results of the optimization. It was shown that for the found adaptation of the conductivities, the AP duration, and the progressions of the conduction velocity, effective refractory period, and wavelength (WL) could be restored. The WL was increased by 53.37% compared to the mutation and had a value of 233.48 mm (BCL = 1 s).
The risk stratification of sudden cardiac death after my- ocardial infarction plays an important role in cardiology. It influences the treatment of a patient and the use of im- plantable devices. However, the majority of well known methods for stratifying risk still fail to predict sudden car- diac death with high accuracy. The heart rate turbulence delivers good results that could be complemented by study- ing ECG morphology. For this purpose, the post extrasys- tolic T wave change was studied in this work. 10 patients with structural healthy ventricles were paced in the right ventricular apex and the subsequent response of the heart was measured in the ECG. Complementary, computer sim- ulations of the human transmembrane voltages and poste- rior ECG reconstruction were also carried out. Morpho- logical changes in the post extrasystolic T wave and its restitution to the original shape were measurable in every patient of this study. The patients presented diminished or alternating postectopic T waves and prolongation of T wave duration. However, the simulation does not present significant T wave changes. Furthermore, the new mor- phological parameters do not seem to correlate with the standard HRT parameters.
A. Loewe, Y. Lutz, A. Fabbri, and S. Severi. Severe sinus bradycardia due to electrolyte changes as a pathomechanism of sudden cardiac death in chronic kidney disease patients undergoing hemodialysis. In Heart Rhythm, vol. 15(5S) , pp. S354-S355, 2018
Background: For chronic kidney disease patients undergoing maintenance hemodialysis (HD), the risk to die from sudden cardiac death (SCD) is 14x higher compared to patients with a history of cardiovascular disease and normal kidney function. Traditional SCD risk factors cannot explain this high rate. Two recent human studies using implantable loop recorders surprisingly point towards bradycardia and asystole as the prevailing arrhythmias causing SCD in HD patients. This suggests a decisive role of the sinus node. Objective: To identify the effect of altered electrolyte levels (as systematically occurring in HD patients) on pacemaking in a computational model of human sinus node cells. Methods: We enhanced the Fabbri et al. model of human sinus node cells to account for the dynamic intracellular balance of all considered electrolytes. The model was exposed to clinically relevant extracellular electrolyte concentrations of potassium, sodium, and calcium to study their effect on spontaneous beating rate and underlying pacemaking mechanisms. The level of sympathetic stimulation was kept constant. Results: The beating rate showed a monotonic relationship with altered electrolyte concentrations starting from a baseline value of 72.5bpm. It increased with sodium (70.8-73.8bpm for [Na+]o from 120-150mM), with potassium (70.7-81.9bpm for [K+]o from 3-9mM), and most pronouncedly with calcium (33.5- 133.8bpm for [Ca2+]o from 0.8-3mM). The severe bradycardia under hypocalcemic conditions was due to hyperpolarized maximum diastolic potential and slower diastolic depolarization driven by attenuation of ICaT and INCX, the latter due to depletion of intracellular calcium. Conclusion: Our human computational study suggests that hypocalcemia causes a pronounced decrease of cellular sinus node pacing rate, which may be a relevant mechanism in HD patients. While increased sympathetic tone will likely compensate the lower basal beating rate, patients developing severe hypocalcaemia are at high risk to experience severe bradycardia and die from SCD during a sudden loss of sympathetic tone.
A. Loewe, Y. Lutz, A. Fabbri, S. Severi, G. Seemann, and D. Dössel. Influence of Electrolyte Concentration Changes on Sinus Node Function - A new Player Regarding Sudden Cardiac Death in Patients with Chronic Kidney Disease?. In Gordon Research Conference on Cardiac Arrhythmia Mechanisms, 2017
Pharmacological therapy of atrial fibrillation (AF) is still a major clinical challenge. Particularly AF of early onset has a significant familiar component and was asso- ciated with various gene mutations. In this study, we de- signed and optimized antiarrhythmic agents for atrial sub- strates affected by human ether-a`-go-go-related gene mu- tations L532P and N588K. A virtual multichannel blocker was designed aiming at a restoration of the wild-type (WT) action potential (AP) on the single cell and tissue level. Furthermore, the amiodarone and dronedarone concen- trations yielding the smallest difference between WT and mutated APs were identified. The WT AP at a basic cy- cle length (BCL) of 1000 ms could be restored by signifi- cant block of IK r and IK ur (\039%) and less pronounced block of IKs, ICa,L, Ib,Na, and Ib,Ca (17%) for both mutations. Effective dronedarone concentrations of 88 nM for L532P and 40 nM for N588K yielded matches almost as good while amiodarone could not sufficiently restore the WT AP. APD90 restitution was effectively restored by the tuned N588K agent whereas differences of up to 34 ms were observed for low BCLs using the tuned L532P agent. Our results provide insight into the pharmacodynamic re- sponse of mutated myocytes and may aid in the optimiza- tion of patient group-specific therapeutic approaches.
The clinical efficacy in preventing the recurrence of atrial fibrillation (AF) is higher for amiodarone than for dronedarone. Moreover, pharmacotherapy with these drugs is less successful in patients with remodeled substrate induced by chronic AF (cAF) and patients suffering from familial AF. To date, the reasons for these phenomena are only incompletely understood. We analyzed the effects of these two drugs in a computational model of atrial electrophysiology. The Courtemanche-Ramirez-Nattel model was adapted to represent cAF remodeled tissue and hERG mutations N588K and L532P. The pharmacodynamics of amiodarone and dronedarone were investigated with respect to their dose and heart rate dependence by evaluating 10 descriptors of action potential morphology and conduction properties. An arrhythmia score was computed based on a subset of these biomarkers and analyzed regarding circadian variation of drug concentration and heart rate. Action potential alternans at high frequencies was observed over the whole dronedarone concentration range at high frequencies, while amiodarone caused alternans only in a narrow range. The total score of dronedarone reached critical values in most of the investigated dynamic scenarios, while amiodarone caused only minor score oscillations. Compared with the other substrates, cAF showed significantly different characteristics resulting in a lower amiodarone but higher dronedarone concentration yielding the lowest score. Significant differences exist in the frequency and concentration-dependent effects between amiodarone and dronedarone and between different atrial substrates. Our results provide possible explanations for the superior efficacy of amiodarone and may aid in the design of substrate-specific pharmacotherapy for AF.
The sinoatrial node (SAN) is the normal pacemaker of the mammalian heart. Over several decades, a large amount of data on the ionic mechanisms underlying the spontaneous electrical activity of SAN pacemaker cells has been obtained, mostly in experiments on single cells isolated from rabbit SAN. This wealth of data has allowed the development of mathematical models of the electrical activity of rabbit SAN pacemaker cells. However, the translation of animal data/models to humans is not straightforward. Even less so for SAN pacemaker cells than working myocar- dial cells given the big di↵erence in their main output (i.e. pacing rate) between human and laboratory animals. The development of a comprehensive model of the electrical activity of a human SAN pacemaker cell strictly based on and constrained by the available electrophysiological data will be presented. We started from the Severi-DiFrancesco rabbit SAN model, which integrates the two principal mecha- nisms that determine the beating rate: the ”membrane clock” and ”calcium clock”. Several current formulations were updated based on available measurements. A set of parameters, for which no specific data were available, were automatically opti- mized to reproduce the measured AP and calcium transient data. The model was then validated by assessing the e↵ects of several mutations a↵ecting heart rate and rate modulation. Moreover, two recent applications of the model will be presented: i) We used our SAN AP computational model to assess the e↵ects of the inclu- sion of the small conductance K+ current (ISK) on the biomarkers that describe the AP waveform and calcium transient; ii) We analysed the e↵ect of altered elec- trolyte levels (as systematically occurring in hemodialysis patients) on pacemaking to investigate the possible mechanisms of the bradycardic sudden cardiac deaths pointed out by two recent human studies using implantable loop recorders.
Student Theses (2)
Y. Lutz. Influence of electrolyte change on sinus node function. A new player regarding sudden cardiac death in patients with chronic kidney disease?. Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT). Masterarbeit. 2016
Chronic kidney disease (CKD) affects more than 30 million patients in the European Union . 25 % of all deaths in this population are due to sudden cardiac death (SCD) [1 5]. Until recently, ventricular fibrillation was assumed to be the main reason. In a 2015 study, Wong et al. showed that bradycardia and asystole are the predominant mecha- nisms of SCD in patients with CKD . This shows that the underlying mechanisms in the pacemaking of the sinoatrial node (SAN) need to be further analyzed. In this work, a computational model of the human SAN by Fabbri et al.  is used to investigate the CKD-induced electrolyte changes on SAN cell electrophysiology. The original model does not show a stable output for low [Ca2+]o. Furthermore, the model lacks a variable formu- lation of [Na+]i. Since low [Ca2+]o occur in heamodialysis patients and variable [Na+]i is required if the electrolyte concentrations change, a model adaption was performed. A simplex-downhill algorithm and the evaluation of several AP markers was used to adapt the dynamics of the L-type calcium current ICaL.The achieved action potential (AP) shape for the model optimization yielded good accor- dance with the AP shape of the original model. Additionally, the adapted model resulted in physiological excitation of APs down to 0.6mM of [Ca2+]o. The unoptimized model exhibited a critical concentration of ≈1.18 mM. A critical concentration range of calcium in the subspace [Ca2+]sub was identified as possible underlying mechanisms for pacemak- ing. Besides the model adaptation, the main part of this work was the evaluation of the impact of electrolyte changes on the model. Therefore, a wide range of maximal and minimal extracellular electrolyte concentrations in HD patients were determined. [Ca2+]o had the most dominant effects in the original and adapted model. Low [Ca2+]o led to a significant increase in cycle length (CL). The longest achieved CL in the original Fabbri et al. model was 2918 ms, which correlated with a +358 % increase compared to reference CL of 814ms. The related low heart rate of 21bpm can be seen as a possible link to the observed bradycardia in HD patients. For increasing calcium concentration the CL declined, resulting in 383 ms for the highest calcium concentration in the original model. The process of extracellular potassium variation was similar to the one for calcium but resulted in less pronounced maximum and minimum values. The resultant changes in the variation of [Na+]o were relatively small. Variable [Na+]i showed compensating effects compared to the original model.In summary, the adaptations in the Fabbri et al. model led to a more stable output for low [Ca2+]o and to the more realistic assumption of variable [Na+]i. In this work, it showed that the variation of [Ca2+]o had dominating effect on the model electrophysiology. In this context, a critical range of [Ca2+]sub was identified as possible mechanism that af- fects pacemaking. The L-type calcium current ICaL was identified as the main pacemaker current, while the influence of the funny current If or the Na+-Ca2+ exchanger INaCa were relatively small in the critical calcium concentration range.
Y. Lutz. Specific antiarrhythmic therapy for familial atrial fibrillation in a numerical model of human atrial electrophysiology. Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT). Bachelorarbeit. 2013
Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting approximately 1% of the population. In general, AF is associated with other cardiac diseases, such as congestive heart failure. However, some patients do not suffer from these comorbidities. Instead, mutations of specific genes have been observed and are supposed to predispose those patients to AF (familial AF). Several anti-arrhythmic agents, which are used in treatment of AF, exist. However, the efficacy of these drugs can still be improved particularly with respect to familial AF. Therefore, the mechanisms of action of these agents have to be better understood and still can be optimized.The aim of this work is to integrate the effects of amiodarone and dronedarone two common anti-arrhythmic drugs - into a model of atrial electrophysiology. Their impact on physiological atrial myocytes, as well as myocytes affected by several mutations shall be investigated.Furthermore, an ideal drug for each mutation shall be identified in terms of reverting electrophysiological parameters to their physiological values on the cellular and tissue level. For this purpose, an appropriate optimization algorithm needs to be designed and implemented.Finally, a comparison of the pharmacological agents and their impact on healthy and mutated tissue shall be carried out.