Rok Hren

Organization of Ventricular Fibrillation in the Human Heart

Sudden cardiac death is a major cause of death in the industrialized world, claiming approximately 300 000 victims annually in the United States alone. In most cases, sudden cardiac death is caused by ventricular fibrillation (VF). Experimental studies in large animal hearts have shown that the uncoordinated contractions during VF are caused by large numbers of chaotically wandering reentrant waves of electrical activity. However, recent clinical data on VF in the human heart seem to suggest that human VF may have a markedly different organization. Here, we use a detailed model of the human ventricles, including a detailed description of cell electrophysiology, ventricular anatomy, and fiber direction anisotropy, to study the organization of human VF. We show that characteristics of our simulated VF are qualitatively similar to the clinical data. Furthermore, we find that human VF is driven by only approximately 10 reentrant sources and thus is much more organized than VF in animal hearts of comparable size, where VF is driven by approximately 50 sources. We investigate the influence of anisotropy ratio, tissue excitability, and restitution properties on the number of reentrant sources driving VF. We find that the number of rotors depends strongest on minimum action potential duration, a property that differs significantly between human and large animal hearts. Based on these findings, we suggest that the simpler spatial organization of human VF relative to VF in large animal hearts may be caused by differences in minimum action potential duration. Both the simpler spatial organization of human VF and its suggested cause may have important implications for treating and preventing this dangerous arrhythmia in humans.

Organization of ventricular fibrillation in the human heart: experiments and models.

Sudden cardiac death is a major health problem in the industrialized world. The lethal event is typically ventricular fibrillation (VF), during which the co‐ordinated regular contraction of the heart is overthrown by a state of mechanical and electrical anarchy. Understanding the excitation patterns that sustain VF is important in order to identify potential therapeutic targets. In this paper, we studied the organization of human VF by combining clinical recordings of electrical excitation patterns on the epicardial surface during in vivo human VF with simulations of VF in an anatomically and electrophysiologically detailed computational model of the human ventricles. We find both in the computational studies and in the clinical recordings that epicardial surface excitation patterns during VF contain around six rotors. Based on results from the simulated three‐dimensional excitation patterns during VF, which show that the total number of electrical sources is 1.4 ± 0.12 times greater than the number of epicardial rotors, we estimate that the total number of sources present during clinically recorded VF is 9.0 ± 2.6. This number is approximately fivefold fewer compared with that observed during VF in dog and pig hearts, which are of comparable size to human hearts. We explain this difference by considering differences in action potential duration dynamics across these species. The simpler spatial organization of human VF has important implications for treatment and prevention of this dangerous arrhythmia. Moreover, our findings underline the need for integrated research, in which human‐based clinical and computational studies complement animal research.

A computational study of mother rotor VF in the human ventricles

Sudden cardiac death is one of the major causes of death in the industrialized world. It is most often caused by a cardiac arrhythmia called ventricular fibrillation (VF). Despite its large social and economical impact, the mechanisms for VF in the human heart yet remain to be identified. Two of the most frequently discussed mechanisms observed in experiments with animal hearts are the multiple wavelet and mother rotor hypotheses. Most recordings of VF in animal hearts are consistent with the multiple wavelet mechanism. However, in animal hearts, mother rotor fibrillation has also been observed. For both multiple wavelet and mother rotor VF, cardiac heterogeneity plays an important role. Clinical data of action potential restitution measured from the surface of human hearts have been recently published. These in vivo data show a substantial degree of spatial heterogeneity. Using these clinical restitution data, we studied the dynamics of VF in the human heart using a heterogeneous computational model of human ventricles. We hypothesized that this observed heterogeneity can serve as a substrate for mother rotor fibrillation. We found that, based on these data, mother rotor VF can occur in the human heart and that ablation of the mother rotor terminates VF. Furthermore, we found that both mother rotor and multiple wavelet VF can occur in the same heart depending on the initial conditions at the onset of VF. We studied the organization of these two types of VF in terms of filament numbers, excitation periods, and frequency domains. We conclude that mother rotor fibrillation is a possible mechanism in the human heart.

Assessment of regularization techniques for electrocardiographic imaging

A widely used approach to solving the inverse problem in electrocardiography involves computing potentials on the epicardium from measured electrocardiograms (ECGs) on the torso surface. The main challenge of solving this electrocardiographic imaging (ECGI) problem lies in its intrinsic ill-posedness. While many regularization techniques have been developed to control wild oscillations of the solution, the choice of proper regularization methods for obtaining clinically acceptable solutions is still a subject of ongoing research. However there has been little rigorous comparison across methods proposed by different groups. This study systematically compared various regularization techniques for solving the ECGI problem under a unified simulation framework, consisting of both 1) progressively more complex idealized source models (from single dipole to triplet of dipoles), and 2) an electrolytic human torso tank containing a live canine heart, with the cardiac source being modeled by potentials measured on a cylindrical cage placed around the heart. We tested 13 different regularization techniques to solve the inverse problem of recovering epicardial potentials, and found that non-quadratic methods (total variation algorithms) and first-order and second-order Tikhonov regularizations outperformed other methodologies and resulted in similar average reconstruction errors.

Impact of the Pharma Economic Act on Diffusion of Innovation and Reduction of Costs in the Hungarian Prescription Drug Market (2007–2010)

OBJECTIVE In this study, we examined the impact of the Pharma Economic Act, which was introduced in Hungary in 2007. METHODS We used detailed data on the Hungarian prescription drug market, which had been made publicly available by the authorities. We evaluated the effect of the Pharma Economic Act on both dynamic and static efficiencies and also on equity, which has been historically a controversial issue in Hungary. We analyzed the overall prescription drug market and statin and atorvastatin markets; as a proxy for determining dynamic efficiency, we examined the oncology drug market for some specific products (e.g., bortezomib) and the long-acting atypical antipsychotic drugs market. RESULTS There is no denying that the authorities managed to control the overall prescription drug costs; however, they were still paying excessive rents for off-patent drugs. Examples of oncology and long-acting atypical antipsychotic drugs showed that the diffusion of innovation was on per-capita basis at least comparable to G-5 countries. While the share of out-of-pocket co-payments markedly increased and the reimbursement was lowered, the concurrent price decreases often meant that the co-payment per milligram of a given dispensed drug was actually lower than that before the Act, thereby benefiting the patient. CONCLUSIONS It appears that strong mechanisms to control volume rather than price on the supply side (marketing authorization holders) contained the drug expenditure, while offering enough room to strive for innovation. Making data on prescription drug expenditures and associated co-payments publicly available is an item that should be definitely followed by the surrounding jurisdictions.

A COMPARISON OF SIMULATED QRS ISOINTEGRAL MAPS RESULTING FROM PACING AT ADJACENT SITES : IMPLICATIONS FOR THE SPATIAL RESOLUTION OF PACE MAPPING USING BODY SURFACE POTENTIALS

Abstract The precise localization of ventricular tachycardia (VT) foci is a prerequisite for the successful radiofrequency catheter ablation in patients. The purpose of this study was to systematically quantify over what distance adjacent sites in the right ventricular (RV) and left ventricular (LV) epicardium and LV endocardium could be distinguished by inspecting morphological features of QRS isointegral maps using statistical methods. We investigated the spatial resolution of QRS isointegral maps by means of an anatomically accurate computer model of the human ventricular myocardium that incorporates a bidomain model for simulating the realistic activation sequences and the oblique dipole model in combination with the boundary element method for calculating extracardiac potentials. In this model, we intitiated activation sequences at a total of 183 epicardial and 75 LV endocardial pacing sites, positioned in three levels (basal, middle, and apical). For each of the 258 pacing sites, we calculated a set of 10 QRS isointegral maps with added Gaussian noise at 117 leads (covering the anterior and posterior torso) and at 32 leads (covering only the anterior torso), respectively. Sets of maps were then cross correlated and root-mean-square (RMS) values of difference maps were calculated for all possible pairs of pacing sites on the same level. We applied the nonparametric unpaired Kolmogorov—Smirnov test and defined the spatial resolution as the pacing site separation at which the differences in correlation coefficients and RMS differences were significant (level P

Review of regularization techniques in electrocardiographic imaging

Regularization methodologies are an integral part in dealing with ill-posedness of inverse problem in electrocardiograhy, expressed in terms of potential distribution on the epicardium. In order to systematically evaluate various regularization techniques under controlled conditions, we employed progressively more complex idealized source models (from single dipole to triplet of dipoles) to calculate body surface potentials, which served as an input data to the inverse problem. In total, we examined, 13 different regularization techniques and found that non-quadratic methods (total variation algorithms) and first-order and second-order Tikhonov regularizations outperformed other methodologies.

Single-dipole and dual-dipole inverse solutions in electrocardiography

In this study, we closely examined the performance of inverse solution in terms of equivalent dipole source model. To simulate potential distribution on the body surface, we employed an analytical model of a single current dipole (or a pair of current dipoles) placed within the homogeneous isotropic volume conductor consisting of two non-concentric spheres. Using these data, we evaluated the accuracy of recovering both location and orientation of the single or dual dipole sources. In total, we examined 24 different dipole locations and found that the location of fitted single and dual current dipoles virtually coincided with the original source for high S/N ratios. We extended investigation to more complex geometry, where a computer model of the human ventricular myocardium was used to simulate activation sequences initiated at eight sites positioned on the epicardial surface of the atrio-ventricular ring. From these sequences, 117-lead body surface potentials were simulated on a realistic torso surface and were then used to localize single and dual accessory pathways employing single or dual equivalent dipoles. Average localization errors were 5 and 12 mm for the single and the dual accessory pathways, respectively, what could be useful additional information prior to electrophysiological study.