Spiral-wave dynamics in ionically realistic mathematical models for human ventricular tissue: the effects of periodic deformation

We carry out an extensive numerical study of the dynamics of spiral waves of electrical activation, in the presence of periodic deformation (PD) in two-dimensional simulation domains, in the biophysically realistic mathematical models of human ventricular tissue due to (a) ten-Tusscher and Panfilov (the TP06 model) and (b) ten-Tusscher, Noble, Noble, and Panfilov (the TNNPO4 model). We first consider simulations in cable-type domains, in which we calculate the conduction velocity theta and the wavelength lambda of a plane wave; we show that PD leads to a periodic, spatial modulation of theta and a temporally periodic modulation of lambda; both these modulations depend on the amplitude and frequency of the PD. We then examine three types of initial conditions for both TP06 and TNNPO4 models and show that the imposition of PD leads to a rich variety of spatiotemporal patterns in the transmembrane potential including states with a single rotating spiral (RS) wave, a spiral-turbulence (ST) state with a single meandering spiral, an ST state with multiple broken spirals, and a state SA in which all spirals are absorbed at the boundaries of our simulation domain. We find, for both TP06 and TNNPO4 models, that spiral-wave dynamics depends sensitively on the amplitude and frequency of PD and the initial condition. We examine how these different types of spiral-wave states can be eliminated in the presence of PD by the application of low-amplitude pulses by square- and rectangular-mesh suppression techniques. We suggest specific experiments that can test the results of our simulations.

A Comparative Study of Early Afterdepolarization-Mediated Fibrillation in Two Mathematical Models for Human Ventricular Cells

Early afterdepolarizations (EADs), which are abnormal oscillations of the membrane potential at the plateau phase of an action potential, are implicated in the development of cardiac arrhythmias like Torsade de Pointes. We carry out extensive numerical simulations of the TP06 and ORd mathematical models for human ventricular cells with EADs. We investigate the different regimes in both these models, namely, the parameter regimes where they exhibit (1) a normal action potential (AP) with no EADs, (2) an AP with EADs, and (3) an AP with EADs that does not go back to the resting potential. We also study the dependence of EADs on the rate of at which we pace a cell, with the specific goal of elucidating EADs that are induced by slow or fast rate pacing. In our simulations in two-and three-dimensional domains, in the presence of EADs, we find the following wave types: (A) waves driven by the fast sodium current and the L-type calcium current (Na-Ca-mediated waves); (B) waves driven only by the L-type calcium current (Ca-mediated waves); (C) phase waves, which are pseudo-travelling waves. Furthermore, we compare the wave patterns of the various wave-types (Na-Ca-mediated, Ca-mediated, and phase waves) in both these models. We find that the two models produce qualitatively similar results in terms of exhibiting Na-Ca-mediated wave patterns that are more chaotic than those for the Ca-mediated and phase waves. However, there are quantitative differences in the wave patterns of each wave type. The Na-Ca-mediated waves in the ORd model show short-lived spirals but the TP06 model does not. The TP06 model supports more Ca-mediated spirals than those in the ORd model, and the TP06 model exhibits more phase-wave patterns than does the ORd model.

Turbulent states and their transitions in mathematical models for ventricular tissue: The effects of random interstitial fibroblasts

We study the dynamical behaviors of two types of spiral-and scroll-wave turbulence states, respectively, in two-dimensional (2D) and three-dimensional (3D) mathematical models, of human, ventricular, myocyte cells that are attached to randomly distributed interstitial fibroblasts; these turbulence states are promoted by (a) the steep slope of the action-potential-duration-restitution (APDR) plot or (b) early afterdepolarizations (EADs). Our single-cell study shows that (1) the myocyte-fibroblast (MF) coupling G(j) and (2) the number N-f of fibroblasts in an MF unit lower the steepness of the APDR slope and eliminate the EAD behaviors of myocytes; we explore the pacing dependence of such EAD suppression. In our 2D simulations, we observe that a spiral-turbulence (ST) state evolves into a state with a single, rotating spiral (RS) if either (a) G(j) is large or (b) the maximum possible number of fibroblasts per myocyte N-f(max) is large. We also observe that the minimum value of G(j), for the transition from the ST to the RS state, decreases as N-f(max) increases. We find that, for the steep-APDR-induced ST state, once the MF coupling suppresses ST, the rotation period of a spiral in the RS state increases as (1) G(j) increases, with fixed N-f(max), and (2) N-f(max) increases, with fixed G(j). We obtain the boundary between ST and RS stability regions in the N-f(max)-G(j) plane. In particular, for low values of N-f(max), the value of G(j), at the ST-RS boundary, depends on the realization of the randomly distributed fibroblasts; this dependence decreases as N-f(max) increases. Our 3D studies show a similar transition from scroll-wave turbulence to a single, rotating, scroll-wave state because of the MF coupling. We examine the experimental implications of our study and propose that the suppression (a) of the steep slope of the APDR or (b) EADs can eliminate spiral-and scroll-wave turbulence in heterogeneous cardiac tissue, which has randomly distributed fibroblasts.

Terapia periodontal não-cirúrgica reduz pressão arterial, massa ventricular esquerda, disfunção endotelial e níveis plasmáticos de proteína C-reativa, interleucina 6 e fibrinogênio

Evidências recentes sugerem que as doenças periodontais podem desempenhar um papel relevante na etiologia e patogênese de doenças cardiovasculares e hipertensão arterial. A resposta inflamatória, com conseqüente elevação de marcadores sistêmicos como proteína C-reativa, fibrinogênio e interleucina-6, e a disfunção endotelial, podem ser os responsáveis por essa associação. Alguns estudos têm relatado maiores níveis pressóricos, maior massa ventricular esquerda e disfunção endotelial em pacientes com doenças periodontais. Ao mesmo tempo, estudos clínicos vêm mostrando que a terapia periodontal pode levar à redução dos níveis plasmáticos dos marcadores de inflamação e redução do risco cardiovascular. O presente estudo teve como objetivo avaliar os efeitos da terapia periodontal não-cirúrgica em 26 pacientes (idade média de 53.68.0 anos) hipertensos refratários. Foram avaliados marcadores plasmáticos de inflamação (proteína C-reativa, fibrinogênio e interleucina-6), pressão arterial sistólica e diastólica, massa ventricular esquerda e rigidez arterial. A terapia periodontal foi eficaz na redução da média de todos os marcadores de risco cardiovascular avaliados. Os níveis de proteína C-reativa baixaram 0.7mg/dl 6 meses após a terapia periodontal, os de IL-6, 1.6pg/dl e os de fibrinogênio 55.3mg/dl (p<0.01). A pressão arterial sistólica apresentou redução média de 16.7mmHg e a diastólica de 9.6mmHg. A massa ventricular esquerda diminuiu em média 12.9g e a velocidade da onda de pulso, um marcador de rigidez arterial, e consequentemente de disfunção endotelial, apresentou redução de seus valores médios de 0.9m/s (p<0.01). Dessa forma, conclui-se que a terapia periodontal foi eficaz na redução dos níveis de proteína C-reativa, interleucina-6, fibrinogênio, pressão arterial, massa ventricular esquerda e rigidez arterial.

Analysing the contribution of ATM/ATR pathway activation in establishing the premature senescence of E2F1/E2F2-/- bone-marrow-derived macrophages

E2F1 and E2F2 transcription factors have an important role during the regulation of cell cycle. In experiments done with E2F1/E2F2 knockout mice, it has been described that bone-marrow-derived macrophages (BMDM) undergo an early rapid proliferation event related to DNA hyper-replication. As a consequence, DNA damage response (DDR) pathway is triggered and E2F1/E2F2 knockout macrophages enter premature senescence related to G2/M phase arrest. The exact mechanism trough which DNA hyper-replication leads to DDR in absence of E2F1 and E2F2 remains undiscovered. To determine whether the ATR/ATM pathway, the master regulator of G2/M checkpoint, might be the surveillance mechanism in order to regulate uncontrolled proliferation in the DKO model, we monitored and analysis biochemical properties of BMDM cultures in the presence of caffeine, a potent inhibitor of ATM/ATR activity. Our results show that the addition of caffeine abolishes premature senescence in DKO BMDM, stimulates γ-H2AX accumulation and decreases Mcm2 expression.

Muscle wasting in myotonic dystrophies: a model of premature aging

Myotonic dystrophy type 1 (DM1 or Steinert's disease) and type 2 (DM2) are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, while other clinical manifestations such as cardiomyopathy, insulin resistance and cataracts are also common. From a clinical perspective, most DM symptoms are interpreted as a result of an accelerated aging (cataracts, muscular weakness and atrophy, cognitive decline, metabolic dysfunction, etc.), including an increased risk of developing tumors. From this point of view, DM1 could be described as a progeroid syndrome since a notable age dependent dysfunction of all systems occurs. The underlying molecular disorder in DM1 consists of the existence of a pathological (CTG) triplet expansion in the 3' untranslated region (UTR) of the Dystrophia ll/Iyotonica Protein Kinase (DMPK) gene, whereas (CCTG)n repeats in the first intron of the Cellular Nucleic acid Binding Protein/Zinc Finger Protein 9 (CNBP/ZNF9) gene cause DM2. The expansions are transcribed into (CUG)n and (CCUG)n-containing RNA, respectively, which form secondary structures and sequester RNA binding proteins, such as the splicing factor muscleblind-like protein (MBNL), forming nuclear aggregates known as foci. Other splicing factors, such as CUGBP, are also disrupted, leading to a spliceopathy of a large number of downstream genes linked to the clinical features of these diseases. Skeletal muscle regeneration relies on muscle progenitor cells, known as satellite cells, which are activated after muscle damage, and which proliferate and differentiate to muscle cells, thus regenerating the damaged tissue. Satellite cell dysfunction seems to be a common feature of both age-dependent muscle degeneration (sarcopenia) and muscle wasting in DM and other muscle degenerative diseases. This review aims to describe the cellular, molecular and macrostructural processes involved in the muscular degeneration seen in DM patients, highlighting the similarities found with muscle aging.

An extended computational model of the circulatory system for designing ventricular assist devices.

An extended computational model of the circulatory system has been developed to predict blood flow in the presence of ventricular assist devices (VADs). A novel VAD, placed in the descending aorta, intended to offload the left ventricle (LV) and augment renal perfusion is being studied. For this application, a better understanding of the global hemodynamic response of the VAD, in essence an electrically driven pump, and the cardiovascular system is necessary. To meet this need, a model has been established as a nonlinear, lumped-parameter electrical analog, and simulated results under different states [healthy, congestive heart failure (CHF), and postinsertion of VAD] are presented. The systemic circulation is separated into five compartments and the descending aorta is composed of three components to accurately yield the system response of each section before and after the insertion of the VAD. Delays in valve closing time and blood inertia in the aorta were introduced to deliver a more realistic model. Pump governing equations and optimization are based on fundamental theories of turbomachines and can serve as a practical initial design point for rotary blood pumps. The model's results closely mimic established parameters for the circulatory system and confirm the feasibility of the intra-aortic VAD concept. This computational model can be linked with models of the pump motor to provide a valuable tool for innovative VAD design.

Short- and long-term changes in joint co-contraction associated with motor learning as revealed from surface EMG.

In the field of motor control, two hypotheses have been controversial: whether the brain acquires internal models that generate accurate motor commands, or whether the brain avoids this by using the viscoelasticity of musculoskeletal system. Recent observations on relatively low stiffness during trained movements support the existence of internal models. However, no study has revealed the decrease in viscoelasticity associated with learning that would imply improvement of internal models as well as synergy between the two hypothetical mechanisms. Previously observed decreases in electromyogram (EMG) might have other explanations, such as trajectory modifications that reduce joint torques. To circumvent such complications, we required strict trajectory control and examined only successful trials having identical trajectory and torque profiles. Subjects were asked to perform a hand movement in unison with a target moving along a specified and unusual trajectory, with shoulder and elbow in the horizontal plane at the shoulder level. To evaluate joint viscoelasticity during the learning of this movement, we proposed an index of muscle co-contraction around the joint (IMCJ). The IMCJ was defined as the summation of the absolute values of antagonistic muscle torques around the joint and computed from the linear relation between surface EMG and joint torque. The IMCJ during isometric contraction, as well as during movements, was confirmed to correlate well with joint stiffness estimated using the conventional method, i.e., applying mechanical perturbations. Accordingly, the IMCJ during the learning of the movement was computed for each joint of each trial using estimated EMG-torque relationship. At the same time, the performance error for each trial was specified as the root mean square of the distance between the target and hand at each time step over the entire trajectory. The time-series data of IMCJ and performance error were decomposed into long-term components that showed decreases in IMCJ in accordance with learning with little change in the trajectory and short-term interactions between the IMCJ and performance error. A cross-correlation analysis and impulse responses both suggested that higher IMCJs follow poor performances, and lower IMCJs follow good performances within a few successive trials. Our results support the hypothesis that viscoelasticity contributes more when internal models are inaccurate, while internal models contribute more after the completion of learning. It is demonstrated that the CNS regulates viscoelasticity on a short- and long-term basis depending on performance error and finally acquires smooth and accurate movements while maintaining stability during the entire learning process.

A controller for a miniature intra-aortic ventricular assist device.

Two control algorithms have been developed for a minimally invasive axial-flow ventricular assist device (VAD) for placement in the descending aorta. The purpose of the device is to offload the left ventricle and to augment lower body perfusion in patients with moderate congestive heart failure. The VAD consists of an intra-aortic impeller with a built-in permanent magnet rotor and an extra-aortic stator. The control algorithms, which use pressure readings upstream and downstream of the VAD to determine the pump status, have been tested in a mock circulatory system under two conditions, namely with or without afterload sensitivity. The results give an insight into controller design for an intra-aortic blood pump working in series with the heart.

Design method of an innovative motor for an intra-aortic ventricular assist device

A permanent-magnet motor has been designed for an innovative axial-flow ventricular assist device (VAD), to be placed in the descending aorta, intended to offload the left ventricle and augment renal perfusion in patients with congestive heart failure (CHF). For this application, an intra-aortic impeller with a built-in permanent magnet rotor is driven by an extraaortic stator working in synchronism with the natural heart. To meet this need, a two-dimensional analytical model has been developed in the MATLAB environment to estimate machine parameters; finite element analysis (FEA) has been used to refine the results. A prototype blood pump equipped with an innovative motor designed from the procedure above has been tested in a mock loop representing the human circulatory system. The performance of VAD incorporating the motor is presented. © 2009 IEEE.