Faculty Opinions recommendation of Pharmacological modulation of cardiac gap junctions to enhance cardiac conduction: evidence supporting a novel target for antiarrhythmic therapy.

AbstractGap junctions are key mediators of the intercellular communication in cardiac tissue, and their function is vital to sustain normal cardiac electrical activity. Conduction through gap junctions strongly depends on the hemichannel arrangement and transjunctional voltage, rendering the intercellular conductance highly non-Ohmic. Despite this marked non-linear behavior, current tissue-level models of cardiac conduction are rooted on the assumption that gap-junctions conductance is constant (Ohmic), which results in inaccurate predictions of electrical propagation, particularly in the low junctional-coupling regime observed under pathological conditions. In this work, we present a novel non-Ohmic multiscale (NOM) model of cardiac conduction that is suitable for tissue-level simulations. Using non-linear homogenization theory, we develop a conductivity model that seamlessly upscales the voltage-dependent conductance of gap junctions, without the need of explicitly modeling gap junctions. The NOM model allows for the simulation of electrical propagation in tissue-level cardiac domains that accurately resemble that of cell-based microscopic models for a wide range of junctional coupling scenarios, recovering key conduction features at a fraction of the computational complexity. A unique feature of the NOM model is the possibility of upscaling the response of non-symmetric gap-junction conductance distributions, which result in conduction velocities that strongly depend on the direction of propagation, thus allowing to model the normal and retrograde conduction observed in certain regions of the heart. We envision that the NOM model will enable organ-level simulations that are informed by sub- and inter-cellular mechanisms, delivering an accurate and predictive in-silico tool for understanding the heart function.Author summaryThe heart relies on the propagation of electrical impulses that are mediated gap junctions, whose conduction properties vary depending on the transjunctional voltage. Despite this non-linear feature, current mathematical models assume that cardiac tissue behaves like an Ohmic (linear) material, thus delivering inaccurate results when simulated in a computer. Here we present a novel mathematical multiscale model that explicitly includes the non-Ohmic response of gap junctions in its predictions. Our results show that the proposed model recovers important conduction features modulated by gap junctions at a fraction of the computational complexity. This contribution represents an important step towards constructing computer models of a whole heart that can predict organ-level behavior in reasonable computing times.

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A Map of the Heart: Gap Junctions, Connexin Diversity and Retroviral Studies of Conduction Myocyte Lineage

Clinical Science ◽

10.1042/cs0880257 ◽

1995 ◽

Vol 88 (3) ◽

pp. 257-262 ◽

Cited By ~ 17

Author(s):

Robert G. Gourdie

Keyword(s):

Gap Junctions ◽

Imaging Techniques ◽

Three Dimensional ◽

Electrical Current ◽

Distribution Patterns ◽

Electrical Contacts ◽

Cardiac Conduction ◽

Developing Heart ◽

Heart Muscle Cells ◽

And Function

1. The heartbeat is co-ordinated by organized propagation of electrical excitation through cardiac muscle. Intercellular conduction and propagation of the cardiac action potential is dependent on electrical connections between myocytes, termed gap junctions. 2. In the last few years, our conception of the structure and function of cardiac gap junctions has been revised substantially. It seems that these structures show unexpected levels of specialization within the myocardium and they can no longer be viewed simply as passive conduits for the regulated movement of electrical current between heart muscle cells. 3. In this article, some of the contributions to this field by the author and his collaborators are summarized. Studies using confocal microscopy and digital imaging techniques to characterize the three-dimensional organization of electrical contacts between myocytes in the mature and developing heart are described, data on the unique expression and spatial distribution patterns of gap-junctional subunit proteins (connexins) are given, and finally the author's current work on the differentiation of cardiac conduction tissues, and how this work arose from studies of gap junctions in the heart, is introduced.

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THE STOCHASTIC NATURE OF CARDIAC PROPAGATION DUE TO THE DISCRETE CELLULAR STRUCTURE OF THE MYOCARDIUM

International Journal of Bifurcation and Chaos ◽

10.1142/s0218127496000990 ◽

1996 ◽

Vol 06 (09) ◽

pp. 1637-1656 ◽

Cited By ~ 8

Author(s):

MADISON S. SPACH

Keyword(s):

Gap Junctions ◽

Wave Front ◽

Cellular Structure ◽

Conduction Block ◽

Microscopic Level ◽

Cardiac Conduction ◽

Electrical Load ◽

Stochastic Nature ◽

Myocardial Architecture ◽

Front Movement

The object of this paper is to describe cardiac conduction phenomena caused by the discrete nature of cardiac cellular structure. Recent results show that the myocardial architecture creates inhomogeneities of electrical load at the microscopic level that cause cardiac propagation to be stochastic in nature. That is, the excitatory events during propagation are constantly changing and disorderly in the sense of varying intracellular events and delays between cells. A unique feature of the stochastic nature of cardiac propagation is that electrical boundaries produced by cellular myocardial architecture create inhomogeneities of electrical load that affect conduction inside individual cells and influence conduction delays across gap junctions, as well as at muscle bundle junctions. This process produces discontinuous propagation as a primary reflection of the nonuniformities of electrical load due to the irregular arrangement of the cellular borders and the associated nonuniform distribution of their electrical interconnections. A fundamental consequence of the stochastic nature of normal propagation at a microscopic level is that it provides a major protective effect against arrhythmias by re-establishing the general trend of wave front movement after small variations in excitation events occur. When the diversity at a very small size scale decreases throughout the tissue, such as occurs when there are regularly repeating relatively isolated groups of cells, larger fluctuations of load can develop and be distributed over more cells than occurs normally. The myocardial architecture may then fail to re-establish a smoothed wave front and re-entry can develop. These relatively new discontinuous conduction phenomena provide important theoretical and experimental challenges to synthesize a complete theory linking continuous and discontinuous media as applied to cardiac conduction. The results show that it will be important to distinguish differences in wave front movement and conduction block caused by mechanisms of continuous media versus wave front movement and block imposed by directional or localized changes in cellular connectivity; i.e., the topology of the electrical connections between cells (gap junctions).

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Role of Gap Junctions in Cardiac Conduction and Development

Circulation Research ◽

10.1161/01.res.87.5.346 ◽

2000 ◽

Vol 87 (5) ◽

pp. 346-348 ◽

Cited By ~ 69

Author(s):

Cecilia W. Lo

Keyword(s):

Gap Junctions ◽

Cardiac Conduction

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Very-Low-Density Lipoprotein of Metabolic Syndrome Modulates Gap Junctions and Slows Cardiac Conduction

Scientific Reports ◽

10.1038/s41598-017-11416-5 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 3

Author(s):

Hsiang-Chun Lee ◽

Chih-Chieh Chen ◽

Wei-Chung Tsai ◽

Hsin-Ting Lin ◽

Yi-Lin Shiao ◽

...

Keyword(s):

Metabolic Syndrome ◽

Gap Junctions ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Cardiac Conduction ◽

Very Low Density Lipoprotein ◽

Low Density

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The Key Role of IP6K: A Novel Target for Anticancer Treatments?

Molecules ◽

10.3390/molecules25194401 ◽

2020 ◽

Vol 25 (19) ◽

pp. 4401

Author(s):

Mirko Minini ◽

Alice Senni ◽

Vittorio Unfer ◽

Mariano Bizzarri

Keyword(s):

Gene Expression Regulation ◽

Pharmacological Modulation ◽

Biochemical Pathways ◽

Inositol Pyrophosphates ◽

Anticancer Treatment ◽

Cell Invasiveness ◽

Novel Target ◽

And Migration ◽

Migration Capacity

Inositol and its phosphate metabolites play a pivotal role in several biochemical pathways and gene expression regulation: inositol pyrophosphates (PP-IPs) have been increasingly appreciated as key signaling modulators. Fluctuations in their intracellular levels hugely impact the transfer of phosphates and the phosphorylation status of several target proteins. Pharmacological modulation of the proteins associated with PP-IP activities has proved to be beneficial in various pathological settings. IP7 has been extensively studied and found to play a key role in pathways associated with PP-IP activities. Three inositol hexakisphosphate kinase (IP6K) isoforms regulate IP7 synthesis in mammals. Genomic deletion or enzymic inhibition of IP6K1 has been shown to reduce cell invasiveness and migration capacity, protecting against chemical-induced carcinogenesis. IP6K1 could therefore be a useful target in anticancer treatment. Here, we summarize the current understanding that established IP6K1 and the other IP6K isoforms as possible targets for cancer therapy. However, it will be necessary to determine whether pharmacological inhibition of IP6K is safe enough to begin clinical study. The development of safe and selective inhibitors of IP6K isoforms is required to minimize undesirable effects.

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The adhesion function of the sodium channel beta subunit (β1) contributes to cardiac action potential propagation

eLife ◽

10.7554/elife.37610 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 23

Author(s):

Rengasayee Veeraraghavan ◽

Gregory S Hoeker ◽

Anita Alvarez-Laviada ◽

Daniel Hoagland ◽

Xiaoping Wan ◽

...

Keyword(s):

Action Potential ◽

Sodium Current ◽

Super Resolution ◽

Cardiac Conduction ◽

Impedance Sensing ◽

Action Potential Propagation ◽

Cell Substrate ◽

Resolution Imaging ◽

Novel Target ◽

Ephaptic Coupling

Computational modeling indicates that cardiac conduction may involve ephaptic coupling – intercellular communication involving electrochemical signaling across narrow extracellular clefts between cardiomyocytes. We hypothesized that β1(SCN1B) –mediated adhesion scaffolds trans-activating NaV1.5 (SCN5A) channels within narrow (<30 nm) perinexal clefts adjacent to gap junctions (GJs), facilitating ephaptic coupling. Super-resolution imaging indicated preferential β1 localization at the perinexus, where it co-locates with NaV1.5. Smart patch clamp (SPC) indicated greater sodium current density (INa) at perinexi, relative to non-junctional sites. A novel, rationally designed peptide, βadp1, potently and selectively inhibited β1-mediated adhesion, in electric cell-substrate impedance sensing studies. βadp1 significantly widened perinexi in guinea pig ventricles, and selectively reduced perinexal INa, but not whole cell INa, in myocyte monolayers. In optical mapping studies, βadp1 precipitated arrhythmogenic conduction slowing. In summary, β1-mediated adhesion at the perinexus facilitates action potential propagation between cardiomyocytes, and may represent a novel target for anti-arrhythmic therapies.

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Gap Junctional Communication via Connexin43 between Purkinje Fibers and Working Myocytes Explains the Epicardial Activation Pattern in the Postnatal Mouse Left Ventricle

International Journal of Molecular Sciences ◽

10.3390/ijms22052475 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2475

Author(s):

Veronika Olejnickova ◽

Matej Kocka ◽

Alena Kvasilova ◽

Hana Kolesova ◽

Adam Dziacky ◽

...

Keyword(s):

Left Ventricle ◽

Gap Junctions ◽

Cardiac Pacemaker ◽

Green Fluorescence Protein ◽

Ventricular Myocardium ◽

Cardiac Conduction ◽

Apical Region ◽

Purkinje Fibers ◽

Junctional Communication ◽

Gap Junctional

The mammalian ventricular myocardium forms a functional syncytium due to flow of electrical current mediated in part by gap junctions localized within intercalated disks. The connexin (Cx) subunit of gap junctions have direct and indirect roles in conduction of electrical impulse from the cardiac pacemaker via the cardiac conduction system (CCS) to working myocytes. Cx43 is the dominant isoform in these channels. We have studied the distribution of Cx43 junctions between the CCS and working myocytes in a transgenic mouse model, which had the His-Purkinje portion of the CCS labeled with green fluorescence protein. The highest number of such connections was found in a region about one-third of ventricular length above the apex, and it correlated with the peak proportion of Purkinje fibers (PFs) to the ventricular myocardium. At this location, on the septal surface of the left ventricle, the insulated left bundle branch split into the uninsulated network of PFs that continued to the free wall anteriorly and posteriorly. The second peak of PF abundance was present in the ventricular apex. Epicardial activation maps correspondingly placed the site of the first activation in the apical region, while some hearts presented more highly located breakthrough sites. Taken together, these results increase our understanding of the physiological pattern of ventricular activation and its morphological underpinning through detailed CCS anatomy and distribution of its gap junctional coupling to the working myocardium.

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