Stretch-induced changes in heart rate and rhythm: clinical observations, experiments and mathematical models

Clinical and research data indicate that active and passive changes in the mechanical environment of the heart are capable of influencing both the initiation and the spread of cardiac excitation via pathways that are intrinsic to the heart. This direction of the cross-talk between cardiac electrical and mechanical activity is referred to as mechano-electric feedback (MEF). MEF is thought to be involved in the adjustment of heart rate to changes in mechanical load and would help to explain the precise beat-to-beat regulation of cardiac performance as it occurs even in the recently transplanted (and, thus, denervated) heart. Furthermore, there is clinical evidence that MEF may be involved in mechanical initiation of arrhythmias and fibrillation, as well as in the re-setting of disturbed heart rhythm by 'mechanical' first aid procedures. This review will outline the clinical relevance of cardiac MEF, describe cellular correlates to the responses observed in situ, and discuss the role that quantitative mathematical models may play in identifying the involvement of cardiac MEF in the regulation of heart rate and rhythm.     

Self-organization of the heartbeat as coordination among ventricular myocardial cells through mechano-electrical feedback

To elucidate the mechanism of the self-organizing control of heartbeats, models that include the electrical and mechanical processes of heartbeat are proposed. As the mutual interaction between the two processes, mechano-electrical feedback (MEF), mediated by stretch-activated ionic channels, is considered. Analyses of the models show that coordination of beats among myocardial cells is established by MEF even in the absence of electrical coupling. The coordination of heartbeats is found to show in-phase synchronization under normal conditions, while it is out of phase or irregular under mechanically abnormal conditions. It is concluded that coupling by MEF is important for the self-organization of heartbeats. Received: 4 December 1997 / Accepted in revised form: 29 July 1998     

Mechano-electrical feedback underlying arrhythmias: the atrial fibrillation case

Mechanoelectrical feedback (MEF) has become firmly established as a mechanism in which mechanical forces experienced by myocardial tissue or cell membranes convey alterations in electrophysiologic characteristics of such tissue. Observations to date mainly concern mechanically induced changes in action potential duration, resting and active potential amplitude, enhanced pacemaker frequency, or afterdepolarizations. While some of these changes (i.e. after depolarizations) may give rise to premature beats, a role of MEF in explaining sustained ventricular tachyarrhythmias has so far been elusive. Here, we review recent findings showing that acute atrial dilatation facilitates atrial fibrillation (AF) and that two stretch-activated channel (SAC) blockers (gadolinium and GsMTx-4) are able to suppress stretch-facilitated AF. These findings strongly support a role of MEF and SACs in promoting sustained arrhythmias and point to a new class of antiarrhythmic drugs.     

Relationship between maximal expiratory flows and lung volumes in growing humans

We examined airway vs. lung parenchymal growth, as inferred from maximal expiratory flows (MEF) and lung volumes (V), respectively, to determine whether the interindividual variability of airway size (inferred from MEF) changes during lung growth and whether a young child with large (or small) airways for his parenchymal size (inferred from V) maintains relatively large (or small) airways for his lung size as he grows to adulthood. Serial measurements of MEF and V were obtained from a cohort of healthy 6- to 27-yr-old males (n = 26) and females (n = 21) over a period of 18 yr. Data were analyzed using logarithmic transformation of the power law equation, MEF = aVb, to fit a regression line to each subject's data points. These growth trajectories were satisfactorily modeled as parallel lines with 20-30% variability of their y-intercepts, indicating that substantial intersubject variability of MEF relative to V is present in early childhood and remains constant during growth. The results further indicate that MEF does track V during lung growth. We conclude that dysanapsis originates in early childhood.     

Phospholipase C-gamma1 is required for survival in heat stress: involvement of protein kinase C-dependent Bcl-2 phosphorylation

The consequences of heat-induced phospholipase C-gamma1 (PLC-gamma1) phosphorylation are not known. We investigated the role of PLC-gamma1 activation and its downstream targets during the cellular response to heat stress using mouse embryonic fibroblasts genetically deficient in PLC-gamma1 (Plcg1 null MEF) and its wild type (wt MEF) as models. Treatment of wt MEF with heat resulted in temperature- and heating duration-dependent tyrosine phosphorylation of PLC-gamma1. HSP70 synthesis and the activation of extracellular signal-regulated kinases 1/2 (ERK1/2) and c-Jun N-terminal protein kinase (JNK) increased equally following heat treatment in both cell lines. However, heat-induced protein kinase C (PKC) activation was dramatically reduced in Plcg1 null MEF compared with wt MEF. Importantly, the mitochondrial localization of PKCalpha, PKC-dependent phosphorylation of Bcl-2, and cell viability in Plcg1 null MEF following heat treatment, were significantly decreased compared with the wild type. Furthermore, pretreatment with bryostatin-1, a PKC activator, enhanced Bcl-2 phosphorylation and cellular resistance to heat-induced apoptosis in Plcg1 null MEF. Taken together, these results suggest that PLC-gamma1 activation enhances cell survival through the PKC-dependent phosphorylation of Bcl-2 during the cellular response to heat stress.     

一套研究机械电反馈的心室压力钳系统

在心脏机械电反馈的研究中准确控制机械刺激是非常重要的。本研究室构建了一套适用于离体家兔心脏的心室压力钳系统。该系统通过计算机控制压力钳,不仅能模拟正常生理条件下左心室的压力波形,还能在心室活动周期的特定时相、以适当波形对心室施加机械刺激。该系统集心脏灌流与起搏、表面心电图记录、单相动作电位记录、心室压力钳制与测定等多种功能于一体,特别适用于器官水平上观察机械电反馈现象并探讨其机制。     

Mechanoelectrical excitation by fluid jets in monolayers of cultured cardiac myocytes.

Although the prevailing view of mechanoelectric feedback (MEF) in the heart is in terms of longitudinal cell stretch, other mechanical forces are considerable during the cardiac cycle, including intramyocardial pressure and shear stress. Their contribution to MEF is largely unknown. In this study, mechanical stimuli in the form of localized fluid jet pulses were applied to neonatal rat ventricular cells cultured as confluent monolayers. Such pulses result in pressure and shear stresses (but not longitudinal stretch) in the monolayer at the point of impingement. The goal was to determine whether these mechanical stimuli can trigger excitation, initiate a propagated wave, and induce reentry. Cells were stained with the voltage-sensitive dye RH237, and multi-site optical mapping was used to record the spread of electrical activity in isotropic and anisotropic monolayers. Pulses (10 ms) with velocities ranging from 0.3 to 1.8 m/s were applied from a 0.4-mm diameter nozzle located 1 mm above the cell monolayer. Fluid jet pulses resulted in circular wavefronts that propagated radially from the stimulus site. The likelihood for mechanical stimulation was quantified as an average stimulus success rate (ASSR). ASSR increased with jet amplitude and time waited between stimuli and decreased with the application of gadolinium and streptomycin, blockers of stretch-activated channels, but not with nifedipine, a blocker of the L-type Ca channel. Absence of cellular injury was confirmed by smooth propagation maps and propidium iodide stains. In rare instances, the mechanical pulse resulted in the induction of reentrant activity. We conclude that mechanical stimuli other than stretch can evoke action potentials, propagated activity, and reentrant arrhythmia in two-dimensional sheets of cardiac cells.     

Modelling and Analysis of Planar Cell Polarity

Planar cell polarity (PCP) occurs in the epithelia of many animals and can lead to the alignment of hairs, bristles, and feathers. Here, we present two approaches to modelling this phenomenon. The aim is to discover the basic mechanisms that drive PCP, while keeping the models mathematically tractable. We present a feedback and diffusion model, in which adjacent cell sides of neighbouring cells are coupled by a negative feedback loop and diffusion acts within the cell. This approach can give rise to polarity, but also to period two patterns. Polarisation arises via an instability provided a sufficiently strong feedback and sufficiently weak diffusion. Moreover, we discuss a conservative model in which proteins within a cell are redistributed depending on the amount of proteins in the neighbouring cells, coupled with intracellular diffusion. In this case, polarity can arise from weakly polarised initial conditions or via a wave provided the diffusion is weak enough. Both models can overcome small anomalies in the initial conditions. Furthermore, the range of the effects of groups of cells with different properties than the surrounding cells depends on the strength of the initial global cue and the intracellular diffusion.     

A Mathematical Framework for Kinetochore-Driven Activation Feedback in the Mitotic Checkpoint

Proliferating cells properly divide into their daughter cells through a process that is mediated by kinetochores, protein–complexes that assemble at the centromere of each sister chromatid. Each kinetochore has to establish a tight bipolar attachment to the spindle apparatus before sister chromatid separation is initiated. The spindle assembly checkpoint (SAC) links the biophysical attachment status of the kinetochores to mitotic progression and ensures that even a single misaligned kinetochore keeps the checkpoint active. The mechanism by which this is achieved is still elusive. Current computational models of the human SAC disregard important biochemical properties by omitting any kind of feedback loop, proper kinetochore signals, and other spatial properties such as the stability of the system and diffusion effects. To allow for more realistic in silico study of the dynamics of the SAC model, a minimal mathematical framework for SAC activation and silencing is introduced. A nonlinear ordinary differential equation model successfully reproduces bifurcation signaling switches with attachment of all 92 kinetochores and activation of APC/C by kinetochore-driven feedback. A partial differential equation model and mathematical linear stability analyses indicate the influence of diffusion and system stability. The conclusion is that quantitative models of the human SAC should account for the positive feedback on APC/C activation driven by the kinetochores which is essential for SAC silencing. Experimental diffusion coefficients for MCC subcomplexes are found to be insufficient for rapid APC/C inhibition. The presented analysis allows for systems-level understanding of mitotic control, and the minimal new model can function as a basis for developing further quantitative–integrative models of the cell division cycle.     

Brusatol enhances MEF2A expression to inhibit RCC progression through the Wnt signalling pathway in renal cell carcinoma

Renal cell carcinoma (RCC) is the most aggressive subtype of kidney tumour with a poor prognosis and an increasing incidence rate worldwide. Brusatol, an essential active ingredient derived from Brucea javanica, exhibits potent antitumour properties. Our study aims to explore a novel treatment strategy for RCC patients. We predicted 37 molecular targets of brusatol based on the structure of brusatol, and MEF2A (Myocyte Enhancer Factor 2A) was selected as our object through bioinformatic analyses. We employed various experimental techniques, including RT-PCR, western blot, CCK8, colony formation, immunofluorescence, wound healing, flow cytometry, Transwell assays and xenograft mouse models, to investigate the impact of MEF2A on RCC. MEF2A expression was found to be reduced in patients with RCC, indicating a close correlation with MEF2A deubiquitylation. Additionally, the protective effects of brusatol on MEF2A were observed. The overexpression of MEF2A inhibits RCC cell proliferation, invasion and migration. In xenograft mice, MEF2A overexpression in RCC cells led to reduced tumour size compared to the control group. The underlying mechanism involves the inhibition of RCC cell proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) through the modulation of Wnt/β-catenin signalling. Altogether, we found that MEF2A overexpression inhibits RCC progression by Wnt/β-catenin signalling, providing novel insight into diagnosis, treatment and prognosis for RCC patients.     

A Simulation Study of the Role of Mechanical Stretch in Arrhythmogenesis during Cardiac Alternans

The deformation of the heart tissue due to the contraction can modulate the excitation, a phenomenon referred to as mechanoelectrical feedback (MEF), via stretch-activated channels. The effects of MEF on the electrophysiology at high pacing rates are shown to be proarrhythmic in general. However, more studies need to be done to elucidate the underlying mechanism. In this work, we investigate the effects of MEF on cardiac alternans, which is an alternation in the width of the action potential that typically occurs when the heart is paced at high rates, using a biophysically detailed electromechanical model of cardiac tissue. We observe that the transition from spatially concordant alternans to spatially discordant alternans, which is more arrhythmogenic than concordant alternans, may occur in the presence of MEF and when its strength is sufficiently large. We show that this transition is due to the increase of the dispersion of conduction velocity. In addition, our results also show that the MEF effects, depending on the stretch-activated channels’ conductances and reversal potentials, can result in blocking action potential propagation.     

Regulator or Driving Force? The Role of Turgor Pressure in Oscillatory Plant Cell Growth

Turgor generates the stress that leads to the expansion of plant cell walls during cellular growth. This has been formalized by the Lockhart equation, which can be derived from the physical laws of the deformation of viscoelastic materials. However, the experimental evidence for such a direct correlation between growth rate and turgor is inconclusive. This has led to challenges of the Lockhart model. We model the oscillatory growth of pollen tubes to investigate this relationship. We couple the Lockhart equation to the dynamical equations for the change in material properties. We find that the correct implementation of the Lockhart equation within a feedback loop leading to low amplitude oscillatory growth predicts that in this system changes in the global turgor do not influence the average growth rate in a linear manner, consistent with experimental observations. An analytic analysis of our model demonstrates in which regime the average growth rate becomes uncorrelated from the turgor pressure.     

Changes in the surface morphology of normal and transformed mouse fibroblasts following disruption of cell-substrate adhesion]

By means of scanning electron microscopy surface morphology of cultured normal mouse embryo fibroblasts (MEF) and transformed mouse fibroblasts of L strain was studied in the course of alteration of cell-substrate adhesion with proteases, EDTA and urea. The morphology of cell rounding induced by the above agents in MEF and L cells was almost independent on the type of the agent. The rounding of MEF proceeded through three stages and was accompanied by substantial changes of cell surface relief. L cells lacked the intermediate stage (formation of thick processes) during their rounding which proceeded without any changes of cell surface relief. It is suggested that the observed differences are related to the poorer development of the lamelloplasm and microfilaments bundles in the transformed cells ascompared to the normal ones.