Eun Bo Shim

Mitochondrial dysfunction and metabolic syndrome—looking for environmental factors

The centerpiece of the pathophysiologic mechanism of metabolic syndrome is insulin resistance. Recently, it is becoming evident that mitochondrial dysfunction is closely related to insulin resistance and metabolic syndrome. The underlying mechanism of mitochondrial dysfunction is very complex, which includes genetic factors from both nuclear and mitochondrial genome and numerous environmental factors. Several mitochondrial DNA polymorphisms are associated with the components of metabolic syndrome. Numerous chemicals and drugs may cause mitochondrial dysfunction and insulin resistance. Notably, it was recently reported that serum levels of several mitochondrial toxins, such as persistent organic pollutants are associated with metabolic syndrome, which necessitates further investigation to reveal its precise mechanism. Given that the health impact of metabolic syndrome is tremendous, it is necessary to develop therapeutic modalities to correct mitochondrial dysfunction or at least to halt its aggravation. In this regard, exercise can improve both mitochondrial function and insulin sensitivity, and some pharmaceutical agents were reported to improve mitochondrial function. However, further studies are warranted to find more effective therapeutic strategies to treat mitochondrial dysfunction. By doing so, we can also shed light on the path of research for other diseases related to mitochondrial dysfunction.

Computational analysis of the effect of the type of LVAD flow on coronary perfusion and ventricular afterload

We developed a computational model to investigate the hemodynamic effects of a pulsatile left ventricular assist device (LVAD) on the cardiovascular system. The model consisted of 16 compartments for the cardiovascular system, including coronary circulation and LVAD, and autonomic nervous system control. A failed heart was modeled by decreasing the end-systolic elastance of the ventricle and blocking the mechanism controlling heart contractility. We assessed the physiological effect of the LVAD on the cardiovascular system for three types of LVAD flow: co-pulsation, counter-pulsation, and continuous flow modes. The results indicated that the pulsatile LVAD with counter-pulsation mode gave the most physiological coronary blood perfusion. In addition, the counter-pulsation mode resulted in a lower peak pressure of the left ventricle than the other modes, aiding cardiac recovery by reducing the ventricular afterload. In conclusion, these results indicate that, from the perspective of cardiovascular physiology, a pulsatile LVAD with counter-pulsation operation is a plausible alternative to the existing LVAD with continuous flow mode.

Comparison of the effects of continuous and pulsatile left ventricular-assist devices on ventricular unloading using a cardiac electromechanics model

Left ventricular-assist devices (LVADs) are used to supply blood to the body of patients with heart failure. Pressure unloading is greater for counter-pulsating LVADs than for continuous LVADs. However, several clinical trials have demonstrated that myocardial recovery is similar for both types of LVAD. This study examined the contractile energy consumption of the myocardium with continuous and counter-pulsating LVAD support to ascertain the effect of the different LVADs on myocardial recovery. We used a three-dimensional electromechanical model of canine ventricles, with models of the circulatory system and an LVAD. We compared the left ventricular peak pressure (LVPP) and contractile ATP consumption between pulsatile and continuous LVADs. With the continuous and counter-pulsating LVAD, the LVPP decreased to 46 and 10%, respectively, and contractile ATP consumption decreased to 60 and 50%. The small difference between the contractile ATP consumption of these two types of LVAD may explain the comparable effects of the two types on myocardial recovery.

Validation of Functional State of Coronary Tandem Lesions Using Computational Flow Dynamics

Functional lesion assessment for coronary tandem lesions and its clinical applications have not been thoroughly studied. The aim of this study was to test the hypothesis that the fractional flow reserve (FFR) gradient across an individual stenosis (ΔFFR) during pressure-wire pullback is a surrogate of the relative functional severity of each stenosis in coronary tandem lesions. For in vitro validation, computational flow dynamic modeling of coronary tandem lesion with various degree of stenosis was constructed. For clinical validation, a total of 52 patients (104 lesions) with coronary tandem lesions (2 stenoses along 1 coronary artery) were consecutively enrolled, and tailored stent procedures based on ΔFFR was performed, at first treating the lesion with large ΔFFR and then subsequently reassessing the FFR for the remaining lesion. The coronary stenosis was considered functionally significant and stenting was performed when the FFR of a lesion was ≤0.80. Using in vitro computational flow dynamic modeling, the lesion with the large ΔFFR of the coronary tandem lesion was indicated as the lesion with the greater degree of simulated diameter stenosis. In the clinical cohort, 28 patients (53.8%) had only single-lesion treatment, and stent implantation for 28 lesions (26.9%) was deferred according to the proposed strategy. During the 9-month follow-up period, only 1 repeat revascularization occurred among the deferred lesions. In conclusion, for the treatment of coronary tandem lesions, ΔFFR may be a useful index for prioritizing the treatment sequence and optimizing the stenting procedure. In this way, unnecessary stent implantation can be avoided, with the achievement of favorable functional and clinical outcomes.

A new multi-scale simulation model of the circulation: from cells to system

We developed a comprehensive cell model that simulates the sequential cellular events from membrane excitation to contraction in the human ventricle. By combining this ventricular cell model with a lumped circulation model, we examined how blood pressure dynamics in the ventricle and aorta are related to the cellular processes. To convert cell contraction into ventricular pressure using Laplaces law, we introduced a simple geometric model of a ventricle: one shaped like a thin-walled hemisphere. The force of contraction of a single cell induces tension in the hemispheric ventricular wall, which generates the ventricular and aortic pressures in the lumped circulation model. The time courses of the hemodynamic properties, as well as the volume–pressure trajectory of the left ventricle, were well reproduced. Our multi-scale cardiovascular model, which covers from cardiac cells to the circulatory system, simulates the typical characteristics of heart mechanics, such as the pressure–volume relationship, stroke volume and the effect of the increased maximum free calcium concentration on cardiovascular hemodynamics. To test the cell-circulation coupling characteristics of the model, we simulated the effects of a decrease in L-type calcium channel conductance (cell level) on left ventricular pressure (system level). The variation due to different pacing frequencies for myocyte excitation was also investigated to assess the effects of heart rate on cardiac cells and the circulatory system.

Numerical analysis of blood flow through a stenosed artery using a coupled multiscale simulation method

A global system model of the systemic circulation is combined with a local finite element solution to simulate blood flow in a stenosed coronary artery. Local fluid dynamic issues arise in connection with the detailed flow patterns within the stenosed coronary artery while the global system model is used to simulate the response of the rest of the circulation to the local perturbation. A PISO type finite element technique is employed to compute the local blood flow. The Navier-Stokes equations are solved with the assumption of viscous incompressible flow across the stenosed coronary artery. A detailed lumped parameter model simulates the characteristics of the coronary circulation and is imbedded in a coarse-grained lumped parameter model of the entire cardiovascular system. These two methods are coupled in that the lumped parameter calculations provide the time-dependent boundary conditions for the local finite element calculation. In turn, the local fluid dynamical computation provides estimates for the pressure drop across the stenosis, which is subsequently used to refine the lumped parameter calculation. Results are obtained for an axisymmetric coronary artery model with a stenosis of 90% area reduction over one cardiac cycle. Numerical results show that the flow rate and resistance are strongly coupled. Compared with the flow rate distribution computed from the global simulation with constant resistance, the coupled solution predicts a flow rate with only slight changes. The high flow rate during diastole increases the stenosis pressure drop and resistance. In turn, this increased resistance of the stenosis slightly reduces the flow rate computed in the lumped parameter simulation.

Computational modeling of apoptotic signaling pathways induced by cisplatin

BackgroundApoptosis is an essential property of all higher organisms that involves extremely complex signaling pathways. Mathematical modeling provides a rigorous integrative approach for analyzing and understanding such intricate biological systems.ResultsHere, we constructed a large-scale, literature-based model of apoptosis pathways responding to an external stimulus, cisplatin. Our model includes the key elements of three apoptotic pathways induced by cisplatin: death receptor-mediated, mitochondrial, and endoplasmic reticulum-stress pathways. We showed that cisplatin-induced apoptosis had dose- and time-dependent characteristics, and the level of apoptosis was saturated at higher concentrations of cisplatin. Simulated results demonstrated that the effect of the mitochondrial pathway on apoptosis was the strongest of the three pathways. The cross-talk effect among pathways accounted for approximately 25% of the total apoptosis level.ConclusionsUsing this model, we revealed a novel mechanism by which cisplatin induces dose-dependent cell death. Our finding that the level of apoptosis was affected by not only cisplatin concentration, but also by cross talk among pathways provides in silico evidence for a functional impact of system-level characteristics of signaling pathways on apoptosis.

Patient-Specific Identification of Optimal Ubiquitous Electrocardiogram (U-ECG) Placement Using a Three-Dimensional Model of Cardiac Electrophysiology

A bipolar mini-ECG for ubiquitous healthcare (U-ECG) has been introduced, and various studies using the U-ECG device are in progress. Because it uses two electrodes within a small torso surface area, the design of the U-ECG must be suitable for detecting ECG signals. Using a 3-D model of cardiac electrophysiology, we have developed a simulation method for identifying the optimal placement of U-ECG electrodes on the torso surface. We simulated the heart-torso model to obtain a body surface potential map and ECG waveforms, which were compared with the empirical data. Using this model, we determined the optimal placement of the two U-ECG electrodes, spaced 5 cm apart, for detecting the P, R, and T waves. The ECG data, obtained using the optimal U-ECG placement for a specific wave, showed a clear shape for the target wave, but equivocal shapes for the other waves. The present study provides an efficient simulation method to identify the optimal attachment position and direction of the U-ECG electrodes on the surface of the torso.

Electrophysiological Rotor Ablation in In-Silico Modeling of Atrial Fibrillation: Comparisons with Dominant Frequency, Shannon Entropy, and Phase Singularity

Background Although rotors have been considered among the drivers of atrial fibrillation (AF), the rotor definition is inconsistent. We evaluated the nature of rotors in 2D and 3D in- silico models of persistent AF (PeAF) by analyzing phase singularity (PS), dominant frequency (DF), Shannon entropy (ShEn), and complex fractionated atrial electrogram cycle length (CFAE-CL) and their ablation. Methods Mother rotor was spatiotemporally defined as stationary reentries with a meandering tip remaining within half the wavelength and lasting longer than 5 s. We generated 2D- and 3D-maps of the PS, DF, ShEn, and CFAE-CL during AF. The spatial correlations and ablation outcomes targeting each parameter were analyzed. Results 1. In the 2D PeAF model, we observed a mother rotor that matched relatively well with DF (>9 Hz, 71.0%, p<0.001), ShEn (upper 2.5%, 33.2%, p<0.001), and CFAE-CL (lower 2.5%, 23.7%, p<0.001). 2. The 3D-PeAF model also showed mother rotors that had spatial correlations with DF (>5.5 Hz, 39.7%, p<0.001), ShEn (upper 8.5%, 15.1%, p <0.001), and CFAE (lower 8.5%, 8.0%, p = 0.002). 3. In both the 2D and 3D models, virtual ablation targeting the upper 5% of the DF terminated AF within 20 s, but not the ablations based on long-lasting PS, high ShEn area, or lower CFAE-CL area. Conclusion Mother rotors were observed in both 2D and 3D human AF models. Rotor locations were well represented by DF, and their virtual ablation altered wave dynamics and terminated AF.

Computational analysis of the effect of valvular regurgitation on ventricular mechanics using a 3D electromechanics model

Using a three-dimensional electromechanical model of the canine ventricles with dyssynchronous heart failure, we investigated the relationship between severity of valve regurgitation and ventricular mechanical responses. The results demonstrated that end-systolic tension in the septum and left ventricular free wall was significantly lower under the condition of mitral regurgitation (MR) than under aortic regurgitation (AR). Stroke work in AR was higher than that in MR. On the other hand, the difference in stroke volume between the two conditions was not significant, indicating that AR may cause worse pumping efficiency than MR in terms of consumed energy and performed work.