Search results
Found 12778 matches for
Mechano-sensitivity of cardiac pacemaker function: Pathophysiological relevance, experimental implications, and conceptual integration with other mechanisms of rhythmicity
Cardiac pacemaker cells exhibit spontaneous, rhythmic electrical excitation, termed automaticity. This automatic initiation of action potentials requires spontaneous diastolic depolarisation, whose rate determines normal rhythm generation in the heart. Pacemaker mechanisms have been split recently into: (i) cyclic changes in trans-sarcolemmal ion flows (termed the 'membrane-clock'), and (ii) rhythmic intracellular calcium cycling (the 'calcium-clock'). These two 'clocks' undoubtedly interact, as trans-sarcolemmal currents involved in pacemaking include calcium-carrying mechanisms, while intracellular calcium cycling requires trans-sarcolemmal ion flux as the mechanism by which it affects membrane potential. The split into separate 'clocks' is, therefore, somewhat arbitrary. Nonetheless, the 'clock' metaphor has been conceptually stimulating, in particular since there is evidence to support the view that either 'clock' could be sufficient in principle to set the rate of pacemaker activation. Of course, the same has also been shown for sub-sets of 'membrane-clock' ion currents, illustrating the redundancy of mechanisms involved in maintaining such basic functionality as the heartbeat, a theme that is common for vital physiological systems. Following the conceptual path of identifying individual groups of sub-mechanisms, it is important to remember that the heart is able to adapt pacemaker rate to changes in haemodynamic load, even after isolation or transplantation, and on a beat-by-beat basis. Neither the 'membrane-' nor the 'calcium-clock' do, as such, inherently account for this rapid adaptation to circulatory demand (cellular Ca 2+ balance changes over multiple beats, while variation of sarcolemmal ion channel presence takes even longer). This suggests that a third set of mechanisms must be involved in setting the pace. These mechanisms are characterised by their sensitivity to the cyclically changing mechanical environment, and - in analogy to the above terminology - this might be considered a 'mechanics-clock'.In this review, we discuss possible roles of mechano-sensitive mechanisms for the entrainment of membrane current dynamics and calcium-handling. This can occur directly via stretch-activation of mechano-sensitive ion channels in the sarcolemma and/or in intracellular membrane compartments, as well as by modulation of 'standard' components of the 'membrane-' or 'calcium-clock'. Together, these mechanisms allow rapid adaptation to changes in haemodynamic load, on a beat-by-beat basis. Additional relevance arises from the fact that mechano-sensitivity of pacemaking may help to explain pacemaker dysfunction in mechanically over- or under-loaded tissue. As the combined contributions of the various underlying oscillatory mechanisms are integrated at the pacemaker cell level into a single output - a train of pacemaker action potentials - we will not adhere to a metaphor that implies separate time-keeping units ('clocks'), and rather focus on cardiac pacemaking as the result of interactions of a set of coupled oscillators, whose individual contributions vary depending on the pathophysiological context. We conclude by considering the utility and limitations of viewing the pacemaker as a coupled system of voltage-, calcium-, and mechanics-modulated oscillators that, by integrating a multitude of inputs, offers the high level of functional redundancy that is vitally important for cardiac automaticity. © 2012 Elsevier Ltd.
Rabbit-specific ventricular model of cardiac electrophysiological function including specialized conduction system
The function of the ventricular specialized conduction system in the heart is to ensure the coordinated electrical activation of the ventricles. It is therefore critical to the overall function of the heart, and has also been implicated as an important player in various diseases, including lethal ventricular arrhythmias such as ventricular fibrillation and drug-induced torsades de pointes. However, current ventricular models of electrophysiology usually ignore, or include highly simplified representations of the specialized conduction system. Here, we describe the development of an image-based, species-consistent, anatomically-detailed model of rabbit ventricular electrophysiology that incorporates a detailed description of the free-running part of the specialized conduction system. Techniques used for the construction of the geometrical model of the specialized conduction system from a magnetic resonance dataset and integration of the system model into a ventricular anatomical model, developed from the same dataset, are described. Computer simulations of rabbit ventricular electrophysiology are conducted using the novel anatomical model and rabbit-specific membrane kinetics to investigate the importance of the components and properties of the conduction system in determining ventricular function under physiological conditions. Simulation results are compared to panoramic optical mapping experiments for model validation and results interpretation. Full access is provided to the anatomical models developed in this study. © 2011 Elsevier Ltd.
For rat's sake: Building an artificial heart
The development of computer models of heart for biomedical research is discussed. Modern engineering technique such as micro-fluidic techniques to deposit patterns of extracellular matrix proteins on elastic membranes, to pre-determine cell growth and cell attachment are applied to study the cardiac structure and electro-mechanical function of flat heart. Computer models of heart are being developed and the most complex model combine realistic tissue architecture with detailed representation of cellular activity, coronary blood flow, and cardiac mechanics. Cardiac modelling offers a valuable compromise for the investigation of many aspects of structure-function interrelation.
Interrogation of living myocardium in multiple static deformation states with diffusion tensor and diffusion spectrum imaging
© 2014 The Authors. Diffusion tensor magnetic resonance imaging (MRI) reveals valuable insights into tissue histo-anatomy and microstructure, and has steadily gained traction in the cardiac community. Its wider use in small animal cardiac imaging invivo has been constrained by its extreme sensitivity to motion, exaggerated by the high heart rates usually seen in rodents. Imaging of the isolated heart eliminates respiratory motion and, if conducted on arrested hearts, cardiac pulsation. This serves as an important intermediate step for basic and translational studies. However, investigating the micro-structural basis of cardiac deformation in the same heart requires observations in different deformation states. Here, we illustrate the imaging of isolated rat hearts in three mechanical states mimicking diastole (cardioplegic arrest), left-ventricular (LV) volume overload (cardioplegic arrest plus LV balloon inflation), and peak systole (lithium-induced contracture). An optimised MRI-compatible Langendorff perfusion setup with the radio-frequency (RF) coil integrated into the wet chamber was developed for use in a 9.4T horizontal bore scanner. Signal-to-noise ratio improved significantly, by 75% compared to a previous design with external RF coil, and stability tests showed no significant changes in mean T1, T2 or LV wall thickness over a 170min period. In contracture, we observed a significant reduction in mean fractional anisotropy from 0.32±0.02 to 0.28±0.02, as well as a significant rightward shift in helix angles with a decrease in the proportion of left-handed fibres, as referring to the locally prevailing cell orientation in the heart, from 24.9% to 23.3%, and an increase in the proportion of right-handed fibres from 25.5% to 28.4%. LV overload, in contrast, gave rise to a decrease in the proportion of left-handed fibres from 24.9% to 21.4% and an increase in the proportion of right-handed fibres from 25.5% to 26.0%. The modified perfusion and coil setup offers better performance and control over cardiac contraction states. We subsequently performed high-resolution diffusion spectrum imaging (DSI) and 3D whole heart fibre tracking in fixed exvivo rat hearts in slack state and contracture. As a model-free method, DSI augmented the measurements of water diffusion by also informing on multiple intra-voxel diffusion orientations and non-Gaussian diffusion. This enabled us to identify the transition from right- to left-handed fibres from the subendocardium to the subepicardium, as well as voxels in apical regions that were traversed by multiple fibres. We observed that both the mean generalised fractional anisotropy and mean kurtosis were lower in hearts in contracture compared to the slack state, by 23% and 9.3%, respectively. While its heavy acquisition burden currently limits the application of DSI invivo, ongoing work in acceleration techniques may enable its use in live animals and patients. This would provide access to the as yet unexplored dimension of non-Gaussian diffusion that could serve as a highly sensitive marker of cardiac micro-structural integrity.