Structure–Function Relationship in the Sinus and Atrioventricular Nodes

Nikolaidou, Theodora; Aslanidi, Oleg; Zhang, H.; Efimov, Igor R.

doi:10.1007/s00246-012-0249-0

Cited by 41 publications

(27 citation statements)

References 68 publications

(144 reference statements)

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“…Other cells, including fibroblasts, may influence changes in BR, 47 as long as they express SAC NS , 48 alter their membrane potential with stretch, 30 and are electrically coupled to SAN myocytes. 49 It is necessary also to consider effects of heterogeneous tissue structure, electrophysiology, and mechanics, given that regional differences affect the extent of, and response to, stretch experienced by individual cells in different parts of the pacemaker tissue 50–52 (parameters that furthermore are age-, 39 species-, 53 and probably disease-dependent). Future computational and experimental research in this area will need to focus on an integrative approach to account for these tissue-level considerations.…”

Section: Wet/dry Integration: From Micro To Macromentioning

confidence: 99%

Combining wet and dry research: experience with model development for cardiac mechano-electric structure-function studies

Quinn

Kohl

2013

Cardiovascular Research

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Since the development of the first mathematical cardiac cell model 50 years ago, computational modelling has become an increasingly powerful tool for the analysis of data and for the integration of information related to complex cardiac behaviour. Current models build on decades of iteration between experiment and theory, representing a collective understanding of cardiac function. All models, whether computational, experimental, or conceptual, are simplified representations of reality and, like tools in a toolbox, suitable for specific applications. Their range of applicability can be explored (and expanded) by iterative combination of ‘wet’ and ‘dry’ investigation, where experimental or clinical data are used to first build and then validate computational models (allowing integration of previous findings, quantitative assessment of conceptual models, and projection across relevant spatial and temporal scales), while computational simulations are utilized for plausibility assessment, hypotheses-generation, and prediction (thereby defining further experimental research targets). When implemented effectively, this combined wet/dry research approach can support the development of a more complete and cohesive understanding of integrated biological function. This review illustrates the utility of such an approach, based on recent examples of multi-scale studies of cardiac structure and mechano-electric function.

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Section: Wet/dry Integration: From Micro To Macromentioning

confidence: 99%

Combining wet and dry research: experience with model development for cardiac mechano-electric structure-function studies

Quinn

Kohl

2013

Cardiovascular Research

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“…From there it divides into the right and left bundle branches at either side of the septum. This description is a simplified version of the conduction pathways distal to the AVN as it is increasingly clear that specialized conduction structures also exit inferiorly from the node forming rings around the mitral and tricuspid valves and a retroaortic node (Yanni et al, 2009, Nikolaidou et al, 2012). These structures have not been as extensively described as the other conduction system compartments, but are slowly becoming better understood from morphological and electrophysiological perspectives.…”

Section: Structure and Function Of The Specialized Conduction Systemmentioning

confidence: 99%

Cell Junctions in the Specialized Conduction System of the Heart

Mezzano

Pellman

Sheikh

2014

Cell Communication & Adhesion

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Anchoring cell junctions are integral in maintaining electro-mechanical coupling of ventricular ‘working’ cardiomyocytes; however, their role in cardiomyocytes of the cardiac conduction system (CCS) remains less clear. Recent studies in genetic mouse models and humans highlight the appearance of these cell junctions alongside gap junctions in the CCS and also show that defects in these structures and their components are associated with conduction impairments in the CCS. Here we outline current evidence supporting an integral relationship between anchoring and gap junctions in the CCS. Specifically we focus on (1) molecular and ultrastructural evidence for cell-cell junctions in specialized cardiomyocytes of the CCS, (2) genetic mouse models specifically targeting cell-cell junction components in the heart which exhibit CCS conduction defects and (3) human clinical studies from patients with cell-cell junction-based diseases that exhibit CCS electrophysiological defects.

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“…This could make electrical invasion of the atria more secure or faster during physiological levels of stretch (while disease-related changes in regional tissue mechanics could have deleterious effects). This will depend greatly on the pre-existing structural complexity of the SAN, which will result in regional differences in stretch sensing, and variation across species (Nikolaidou et al., 2012). An additional mechanism worth considering is a possible change in the inherent mechano-sensitivity of SAN cells that may occur with disease or age, due to changes in expression and activity of mechano-sensitive channels (Boyett, 2009; Stones et al., 2008; Tellez et al., 2011).…”

Section: The Mechanics-oscillator and Its Patho/physiological Relevancementioning

confidence: 99%

Mechano-sensitivity of cardiac pacemaker function: Pathophysiological relevance, experimental implications, and conceptual integration with other mechanisms of rhythmicity

Quinn

Kohl

2012

Progress in Biophysics and Molecular Biology

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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 Ca2+ 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 osci...

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Structure–Function Relationship in the Sinus and Atrioventricular Nodes

Cited by 41 publications

References 68 publications

Combining wet and dry research: experience with model development for cardiac mechano-electric structure-function studies

Combining wet and dry research: experience with model development for cardiac mechano-electric structure-function studies

Cell Junctions in the Specialized Conduction System of the Heart

Mechano-sensitivity of cardiac pacemaker function: Pathophysiological relevance, experimental implications, and conceptual integration with other mechanisms of rhythmicity

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