Abstract:

Acute ischemic stroke is a major health problem with a high mortality rate and a high risk for permanent disabilities. Selective brain hypothermia has the neuroprotective potential to possibly lower cerebral harm. A recently developed catheter system enables to combine endovascular blood cooling and thrombectomy using the same endovascular access. By using the penumbral perfusion via leptomeningeal collaterals, the catheter aims at enabling a cold reperfusion, which mitigates the risk of a reperfusion injury. However, cerebral circulation is highly patient-specific and can vary greatly. Since direct measurement of remaining perfusion and temperature decrease induced by the catheter is not possible without additional harm to the patient, computational modeling provides an alternative to gain knowledge about resulting cerebral temperature decrease. In this work, we present a brain temperature model with a realistic division into gray and white matter and consideration of spatially resolved perfusion. Furthermore, it includes detailed anatomy of cerebral circulation with possibility of personalizing on base of real patient anatomy. For evaluation of catheter performance in terms of cold reperfusion and to analyze its general performance, we calculated the decrease in brain temperature in case of a large vessel occlusion in the middle cerebral artery (MCA) for different scenarios of cerebral arterial anatomy. Congenital arterial variations in the circle of Willis had a distinct influence on the cooling effect and the resulting spatial temperature distribution before vessel recanalization. Independent of the branching configurations, the model predicted a cold reperfusion due to a strong temperature decrease after recanalization (1.4-2.2  C after 25 min of cooling, recanalization after 20 min of cooling). Our model illustrates the effectiveness of endovascular cooling in combination with mechanical thrombectomy and its results serve as an adequate substitute for temperature measurement in a clinical setting in the absence of direct intraparenchymal temperature probes.

Abstract:

Therapeutic hypothermia (TH) is an approved neuroproctetive treatment to reduce neurological morbidity and mortality after hypoxic-ischemic damage related to cardiac arrest and neonatal asphyxia. Also in the treatment of acute ischemic stroke (AIS), which in Western countries still shows a very high mortality rate of about 25 %, selective mild TH by means of Targeted Temperature Management (TTM) could potentially decrease final infarct volume. In this respect, a novel intracarotid blood cooling catheter system has recently been developed, which allows for combined carotid blood cooling and mechanical thrombectomy (MT) and aims at selective mild TH in the affected ischemic brain (core and penumbra). Unfortunately, so far direct measurement and control of cooled cerebral temperature requires invasive or elaborate MRI-assisted measurements. Computational modeling provides unique opportunities to predict the resulting cerebral temperatures on the other hand. In this work, a simplified 3D brain model was generated and coupled with a 1D hemodynamics model to predict spatio-temporal cerebral temperature profiles using finite element modeling. Cerebral blood and tissue temperatures as well as the systemic temperature were analyzed for physiological conditions as well as for a middle cerebral artery (MCA) M1 occlusion. Furthermore, vessel recanalization and its effect on cerebral temperature was analyzed. The results show a significant influence of collateral flow on the cooling effect and are in accordance with experimental data in animals. Our model predicted a possible neuroprotective temperature decrease of 2.5 ℃ for the territory of MCA perfusion after 60 min of blood cooling, which underlines the potential of the new device and the use of TTM in case of AIS.

Abstract:

Local brain hypothermia is an attractive method for providing cerebral neuroprotection for ischemic stroke patients and at the same time reducing systemic side effects of cooling. In acute ischemic stroke patients with large vessel occlusion, combination with endovascular mechanical recanalization treatment could potentially allow for an alleviation of inflammatory and apoptotic pathways in the critical phase of reperfusion. The direct cooling of arterial blood by means of an intra-carotid heat exchange catheter compatible with recanalization systems is a novel promising approach. Focusing on the concept of "cold reperfusion", we developed an energetic model to calculate the rate of temperature decrease during intra-carotid cooling in case of physiological as well as decreased perfusion. Additionally, we discussed and considered the effect and biological significance of temperature decrease on resulting brain perfusion. Our model predicted a 2 °C brain temperature decrease in 8.3, 11.8 and 26.2 min at perfusion rates of 50, 30 and 10ml100g⋅min, respectively. The systemic temperature decrease - caused by the venous blood return to the main circulation - was limited to 0.5 °C in 60 min. Our results underline the potential of catheter-assisted, intracarotid blood cooling to provide a fast and selective brain temperature decrease in the phase of vessel recanalization. This method can potentially allow for a tissue hypothermia during the restoration of the physiological flow and thus a "cold reperfusion" in the setting of mechanical recanalization.

Abstract:

Each heartbeat is initiated by cyclic spontaneous depolarization of cardiomyocytes in the sinus node forming the primary natural pacemaker. In patients with end-stage renal disease undergoing hemodialysis, it was recently shown that the heart rate drops to very low values before they suffer from sudden cardiac death with an unexplained high incidence. We hypothesize that the electrolyte changes commonly occurring in these patients affect sinus node beating rate and could be responsible for severe bradycardia. To test this hypothesis, we extended the Fabbri et al. computational model of human sinus node cells to account for the dynamic intracellular balance of ion concentrations. Using this model, we systematically tested the effect of altered extracellular potassium, calcium, and sodium concentrations. Although sodium changes had negligible (0.15 bpm/mM) and potassium changes mild effects (8 bpm/mM), calcium changes markedly affected the beating rate (46 bpm/mM ionized calcium without autonomic control). This pronounced bradycardic effect of hypocalcemia was mediated primarily by I attenuation due to reduced driving force, particularly during late depolarization. This, in turn, caused secondary reduction of calcium concentration in the intracellular compartments and subsequent attenuation of inward I and reduction of intracellular sodium. Our in silico findings are complemented and substantiated by an empirical database study comprising 22,501 pairs of blood samples and in vivo heart rate measurements in hemodialysis patients and healthy individuals. A reduction of extracellular calcium was correlated with a decrease of heartrate by 9.9 bpm/mM total serum calcium (p < 0.001) with intact autonomic control in the cross-sectional population. In conclusion, we present mechanistic in silico and empirical in vivo data supporting the so far neglected but experimentally testable and potentially important mechanism of hypocalcemia-induced bradycardia and asystole, potentially responsible for the highly increased and so far unexplained risk of sudden cardiac death in the hemodialysis patient population.

Abstract:

Changes of serum and extracellular ion concentrations occur regularly in patients with chronic kidney disease (CKD). Recently, hypocalcemia, i.e. a decrease of the extra-cellular calcium concentration [Ca2+]o, has been suggested as potential pathomechanism contributing to the unexplained high rate of sudden cardiac death (SCD) in CKD patients. In particular, there is a hypothesis that hypocalcaemia could slow down natural pacemaking in the human sinus node to fatal degrees. Here, we address the question whether there are inter-species differences in the response of cellular sinus node pacemaking to changes of [Ca2+]o. Towards this end, we employ computational models of mouse, rabbit and human sinus node cells. The Fabbri et al. human model was updated to consider changes of intracellular ion concentrations. We identified crucial inter-species differences in the response of cellular pacemaking in the sinus node to changes of [Ca2+]o with little changes of cycle length in mouse and rabbit models (<83 ms) in contrast to a pronounced bradycardic effect in the human model (up to > 1000 ms). Our results suggest that experiments with human sinus node cells are required to investigate the potential mechanism of hypocalcaemia-induced bradycardic SCD in CKD patients and small animal models are not well suited.

Abstract:

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.

Abstract:

In Western countries, stroke is the third-most widespread cause of death. 80% of all strokes are ischemic and show a mortality rate of about 25%. Furthermore, 35-55% of affected patients retain a permanent disability. Therapeutic hypothermia (TH) could decrease inflammatory processes and the stroke-induced cerebral damage. Currently, the standard technique to induce TH is cooling of the whole body, which can cause several side effects. A novel cooling sheath uses intra-carotid blood cooling to induce local TH. Unfortunately, the control of the temporal and spatial cerebral temperature course requires invasive temperature measurements. Computational modeling could be used to predict the resulting temperature courses instead. In this work, a detailed 1D hemodynamics model of the cerebral arterial system was coupled with an energetic temperature model. For physiological conditions, 50% and 100% M1-stenoses, the temperatures in the supply area of the middle cerebral artery (MCA) and of the systemic body was analyzed. A 2K temperature decrease was reached within 10min of cooling for physiological conditions and 50% stenosis. For 100% stenosis, a significant lower cooling effect was observed, resulting in a maximum cerebral temperature decrease of 0.7K after 30min of cooling. A significant influence of collateral flow rates on the cooling effect was observed. However, regardless of the stenosis degree, the temperature decrease was strongest within the first 20min of cooling, which demonstrates the fast and effective impact of intra-carotid blood cooling.

Abstract:

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.

Abstract:

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).

Abstract:

Stroke is the third-most cause of death in developed countries. A new promising treatment method in case of an ischemic stroke is selective intracarotid blood cooling combined with mechanical artery recanalization. However, the control of the treatment requires invasive or MRI-assisted measurement of cerebral temperature. An auspicious alternative is the use of computational modeling. In this work, we extended an existing 1D hemodynamics model including the characteristics of the anterior, middle and posterior cerebral artery. Furthermore, seven ipsilateral anastomoses were additionally integrated for each hemisphere. A potential stenosis was placed into the M1 segment of the middle cerebral artery, due to the highest risk of occlusion there. The extended model was evaluated for various degrees of collateralization (“poor”, “partial” and “good”) and degrees of stenosis (0%, 50%, 75% and 99.9%). Moreover, cerebral autoregulation was considered in the model. The higher the degree of collateralization and the degree of stenosis, the higher was the blood flow through the collaterals. Hence, a patient with a good collateralization could compensate a higher degree of occlusion and potentially has a better outcome after an ischemic stroke. For a 99.9% stenosis, an increased summed mean blood flow through the collaterals of +97.7% was predicted in case of good collateralization. Consequently, the blood supply via the terminal branches of the middle cerebral artery could be compensated up to 44.4% to the physiological blood flow. In combination with a temperature model, our model of the cerebral collateral circulation can be used for tailored temperature prediction for patients to be treated with selective therapeutic hypothermia.

Abstract:

In Western countries, stroke is the third-most cause of death; 35- 55% of the survivors experience permanent disability. Mild therapeutic hypothermia (TH) showed neuroprotective effect in patients returning from cardiac arrest and is therefore assumed to decrease stroke induced cerebral damage. Recently, an intracarotid cooling sheath was developed to induce local TH in the penumbra using the cooling effect of cerebral blood flow via collaterals. Computational modeling provides unique opportunities to predict the resulting cerebral temperature without invasive procedures. In this work, we generated a simplified brain model to establish a cerebral temperature calculation using Pennes’ bio-heat equation and a 1D hemodynamics model of the cranial artery tree. In this context, we performed an extensive literature research to assign the terminal segments of the latter to the corresponding perfused tissue. Using the intracarotid cooling method, we simulated the treatment with TH for different degrees of stenosis in the middle cerebral artery (MCA) and analyzed the resulting temperature spatialtemporal distributions of the brain and the systemic body considering the influence of the collaterals on the effect of cooling.

Abstract:

Changes of serum and extracellular ion concentrations occur regularly in patients with chronic kidney disease (CKD). Recently, hypocalcaemia, i.e. a decrease of the extracellular calcium concentration [Ca 2+ ] o , has been suggested as potential pathomechanism contributing to the unexplained high rate of sudden cardiac death (SCD) in CKD patients. In particular, there is a hypothesis that hypocalcaemia could slow down natural pacemaking in the human sinus node to fatal degrees. Here, we address the question whether there are inter-species differences in the response of cellular sinus node pacemaking to changes of [Ca 2+ ] o . Towards this end, we employ computational models of mouse, rabbit and human sinus node cells. The Fabbri et al. human model was updated to consider changes of intracellular ion concentrations. We identified crucial inter-species differences in the response of cellular pacemaking in the sinus node to changes of [Ca 2+ ] o with little changes of cycle length in mouse and rabbit models (<83 ms) in contrast to a pronounced bradycardic effect in the human model (up to >1000 ms). Our results suggest that experiments with human sinus node cells are required to investigate the potential mechanism of hypocalcaemia-induced bradycardic SCD in CKD patients and small animal models are not well suited.

Abstract:

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.

Abstract:

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.

Abstract:

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.

Abstract:

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.

Abstract:

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 (&#63743;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.