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Piero Anversa - One of the best experts on this subject based on the ideXlab platform.
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Myocyte growth in the failing heart
Surgical Clinics of North America, 2004Co-Authors: Jan Kajstura, Bernardo Nadal-ginard, Annarosa Leri, Clotilde Castaldo, Piero AnversaAbstract:: Adult ventricular Myocytes can undergo mitotic division, resulting in an increase in the aggregate number of cells in the heart. The improvement in the methodological approach to the analysis of tissue sections by immunostaining and confocal microscopy has defeated the dogma that Myocyte regeneration cannot occur in the adult heart. Most importantly, primitive and progenitor cells have been identified in the human heart. These cells express telomerase and have the capability of undergoing lineage commitment and rapid cell division, expanding significantly the contracting ventricular myocardium. These cell populations possess all the molecular components regulating the entry and progression through the cell cycle, karyokinesis, and cytokinesis. The recognition that Myocyte hypertrophy and regeneration, as well as Myocyte necrosis and apoptosis, occur in cardiac diseases has contributed to enhancing our understanding of the plasticity of the human heart.
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intense Myocyte formation from cardiac stem cells in human cardiac hypertrophy
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Konrad Urbanek, Annarosa Leri, Jan Kajstura, Federico Quaini, Giordano Tasca, Daniele Torella, Clotilde Castaldo, Bernardo Nadalginard, Eugenio Quaini, Piero AnversaAbstract:Abstract It is generally believed that increase in adult contractile cardiac mass can be accomplished only by hypertrophy of existing Myocytes. Documentation of myocardial regeneration in acute stress has challenged this dogma and led to the proposition that Myocyte renewal is fundamental to cardiac homeostasis. Here we report that in human aortic stenosis, increased cardiac mass results from a combination of Myocyte hypertrophy and hyperplasia. Intense new Myocyte formation results from the differentiation of stem-like cells committed to the Myocyte lineage. These cells express stem cell markers and telomerase. Their number increased >13-fold in aortic stenosis. The finding of cell clusters with stem cells making the transition to cardiogenic and Myocyte precursors, as well as very primitive Myocytes that turn into terminally differentiated Myocytes, provides a link between cardiac stem cells and Myocyte differentiation. Growth and differentiation of these primitive cells was markedly enhanced in hypertrophy, consistent with activation of a restricted number of stem cells that, through symmetrical cell division, generate asynchronously differentiating progeny. These clusters strongly support the existence of cardiac stem cells that amplify and commit to the Myocyte lineage in response to increased workload. Their presence is consistent with the notion that Myocyte hyperplasia significantly contributes to cardiac hypertrophy and accounts for the subpopulation of cycling Myocytes.
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Myocyte death growth and regeneration in cardiac hypertrophy and failure
Circulation Research, 2003Co-Authors: Bernardo Nadalginard, Annarosa Leri, Jan Kajstura, Piero AnversaAbstract:The accepted paradigm considers the adult mammalian heart as a postmitotic organ, which possesses a relatively constant number of Myocytes from shortly after birth to adulthood and senescence. This notion is questioned by the demonstration that although most adult Myocytes are terminally differentiated, there is a small and continuously renewed subpopulation of cycling Myocytes produced by the differentiation of cardiac stem-like cells. Myocyte death and Myocyte regeneration are introduced as major determinants of cardiac homeostasis and alterations of ventricular anatomy and function in physiological and pathological states. The possibility of reconstituting dead myocardium by stem-like cells is advanced and proposed as a major area of future research.
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Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation
EMBO Journal, 2003Co-Authors: Annarosa Leri, Antonella Zacheo, Laura Barlucchi, Stefano Chimenti, Federica Limana, Sonia Franco, Bernardo Nadal-ginard, Jan Kajstura, Piero Anversa, Maria A BlascoAbstract:Cardiac failure is a frequent cause of death in the aging human population. Telomere attrition occurs with age, and is proposed to be causal for the aging process. To determine whether telomere shortening leads to a cardiac phenotype, we studied heart function in the telomerase knockout mouse, Terc-/-. We studied Terc-/- mice at the second, G2, and fifth, G5, generation. Telomere shortening in G2 and G5 Terc-/- mice was coupled with attenuation in cardiac Myocyte proliferation, increased apoptosis and cardiac Myocyte hypertrophy. On a single-cell basis, telomere shortening was coincidental with increased expression of p53, indicating the presence of dysfunctional telomeres in cardiac Myocytes from G5 Terc-/- mice. The impairment in cell division, the enhanced cardiac Myocyte death and cellular hypertrophy, are concomitant with ventricular dilation, thinning of the wall and cardiac dysfunction. Thus, inhibition of cardiac Myocyte replication provoked by telomere shortening, results in de-compensated eccentric hypertrophy and heart failure in mice. Telomere shortening with age could also contribute to cardiac failure in humans, opening the possibility for new therapies.
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Myocyte proliferation and ventricular remodeling
Journal of Cardiac Failure, 2002Co-Authors: Annarosa Leri, Jan Kajstura, Piero AnversaAbstract:Improvement in the methodological approach to the analysis of the myocardium has provided clear evidence of cardiac Myocyte proliferation, questioning the general belief that the growth of the adult heart under physiological and pathological conditions can occur only by cellular hypertrophy. Myocyte regeneration contributes via Myocyte death to the physiological turnover of Myocytes and via Myocyte hypertrophy to cardiac remodeling. Several questions, however, remain to be answered. Among them, it is still unknown whether Myocyte multiplication exerts a positive and/or negative effect on ventricular anatomy and cardiac function. The addition of newly generated Myocytes leads to cavitary dilation with relative thinning of the wall. Conversely, Myocyte proliferation, characterized by the parallel addition of cells, can be expected to increase wall thickness, decrease chamber size, and ameliorate cardiac performance.
Jan Kajstura - One of the best experts on this subject based on the ideXlab platform.
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Myocyte growth in the failing heart
Surgical Clinics of North America, 2004Co-Authors: Jan Kajstura, Bernardo Nadal-ginard, Annarosa Leri, Clotilde Castaldo, Piero AnversaAbstract:: Adult ventricular Myocytes can undergo mitotic division, resulting in an increase in the aggregate number of cells in the heart. The improvement in the methodological approach to the analysis of tissue sections by immunostaining and confocal microscopy has defeated the dogma that Myocyte regeneration cannot occur in the adult heart. Most importantly, primitive and progenitor cells have been identified in the human heart. These cells express telomerase and have the capability of undergoing lineage commitment and rapid cell division, expanding significantly the contracting ventricular myocardium. These cell populations possess all the molecular components regulating the entry and progression through the cell cycle, karyokinesis, and cytokinesis. The recognition that Myocyte hypertrophy and regeneration, as well as Myocyte necrosis and apoptosis, occur in cardiac diseases has contributed to enhancing our understanding of the plasticity of the human heart.
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intense Myocyte formation from cardiac stem cells in human cardiac hypertrophy
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Konrad Urbanek, Annarosa Leri, Jan Kajstura, Federico Quaini, Giordano Tasca, Daniele Torella, Clotilde Castaldo, Bernardo Nadalginard, Eugenio Quaini, Piero AnversaAbstract:Abstract It is generally believed that increase in adult contractile cardiac mass can be accomplished only by hypertrophy of existing Myocytes. Documentation of myocardial regeneration in acute stress has challenged this dogma and led to the proposition that Myocyte renewal is fundamental to cardiac homeostasis. Here we report that in human aortic stenosis, increased cardiac mass results from a combination of Myocyte hypertrophy and hyperplasia. Intense new Myocyte formation results from the differentiation of stem-like cells committed to the Myocyte lineage. These cells express stem cell markers and telomerase. Their number increased >13-fold in aortic stenosis. The finding of cell clusters with stem cells making the transition to cardiogenic and Myocyte precursors, as well as very primitive Myocytes that turn into terminally differentiated Myocytes, provides a link between cardiac stem cells and Myocyte differentiation. Growth and differentiation of these primitive cells was markedly enhanced in hypertrophy, consistent with activation of a restricted number of stem cells that, through symmetrical cell division, generate asynchronously differentiating progeny. These clusters strongly support the existence of cardiac stem cells that amplify and commit to the Myocyte lineage in response to increased workload. Their presence is consistent with the notion that Myocyte hyperplasia significantly contributes to cardiac hypertrophy and accounts for the subpopulation of cycling Myocytes.
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Myocyte death growth and regeneration in cardiac hypertrophy and failure
Circulation Research, 2003Co-Authors: Bernardo Nadalginard, Annarosa Leri, Jan Kajstura, Piero AnversaAbstract:The accepted paradigm considers the adult mammalian heart as a postmitotic organ, which possesses a relatively constant number of Myocytes from shortly after birth to adulthood and senescence. This notion is questioned by the demonstration that although most adult Myocytes are terminally differentiated, there is a small and continuously renewed subpopulation of cycling Myocytes produced by the differentiation of cardiac stem-like cells. Myocyte death and Myocyte regeneration are introduced as major determinants of cardiac homeostasis and alterations of ventricular anatomy and function in physiological and pathological states. The possibility of reconstituting dead myocardium by stem-like cells is advanced and proposed as a major area of future research.
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Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation
EMBO Journal, 2003Co-Authors: Annarosa Leri, Antonella Zacheo, Laura Barlucchi, Stefano Chimenti, Federica Limana, Sonia Franco, Bernardo Nadal-ginard, Jan Kajstura, Piero Anversa, Maria A BlascoAbstract:Cardiac failure is a frequent cause of death in the aging human population. Telomere attrition occurs with age, and is proposed to be causal for the aging process. To determine whether telomere shortening leads to a cardiac phenotype, we studied heart function in the telomerase knockout mouse, Terc-/-. We studied Terc-/- mice at the second, G2, and fifth, G5, generation. Telomere shortening in G2 and G5 Terc-/- mice was coupled with attenuation in cardiac Myocyte proliferation, increased apoptosis and cardiac Myocyte hypertrophy. On a single-cell basis, telomere shortening was coincidental with increased expression of p53, indicating the presence of dysfunctional telomeres in cardiac Myocytes from G5 Terc-/- mice. The impairment in cell division, the enhanced cardiac Myocyte death and cellular hypertrophy, are concomitant with ventricular dilation, thinning of the wall and cardiac dysfunction. Thus, inhibition of cardiac Myocyte replication provoked by telomere shortening, results in de-compensated eccentric hypertrophy and heart failure in mice. Telomere shortening with age could also contribute to cardiac failure in humans, opening the possibility for new therapies.
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Myocyte proliferation and ventricular remodeling
Journal of Cardiac Failure, 2002Co-Authors: Annarosa Leri, Jan Kajstura, Piero AnversaAbstract:Improvement in the methodological approach to the analysis of the myocardium has provided clear evidence of cardiac Myocyte proliferation, questioning the general belief that the growth of the adult heart under physiological and pathological conditions can occur only by cellular hypertrophy. Myocyte regeneration contributes via Myocyte death to the physiological turnover of Myocytes and via Myocyte hypertrophy to cardiac remodeling. Several questions, however, remain to be answered. Among them, it is still unknown whether Myocyte multiplication exerts a positive and/or negative effect on ventricular anatomy and cardiac function. The addition of newly generated Myocytes leads to cavitary dilation with relative thinning of the wall. Conversely, Myocyte proliferation, characterized by the parallel addition of cells, can be expected to increase wall thickness, decrease chamber size, and ameliorate cardiac performance.
Annarosa Leri - One of the best experts on this subject based on the ideXlab platform.
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Myocyte growth in the failing heart
Surgical Clinics of North America, 2004Co-Authors: Jan Kajstura, Bernardo Nadal-ginard, Annarosa Leri, Clotilde Castaldo, Piero AnversaAbstract:: Adult ventricular Myocytes can undergo mitotic division, resulting in an increase in the aggregate number of cells in the heart. The improvement in the methodological approach to the analysis of tissue sections by immunostaining and confocal microscopy has defeated the dogma that Myocyte regeneration cannot occur in the adult heart. Most importantly, primitive and progenitor cells have been identified in the human heart. These cells express telomerase and have the capability of undergoing lineage commitment and rapid cell division, expanding significantly the contracting ventricular myocardium. These cell populations possess all the molecular components regulating the entry and progression through the cell cycle, karyokinesis, and cytokinesis. The recognition that Myocyte hypertrophy and regeneration, as well as Myocyte necrosis and apoptosis, occur in cardiac diseases has contributed to enhancing our understanding of the plasticity of the human heart.
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intense Myocyte formation from cardiac stem cells in human cardiac hypertrophy
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Konrad Urbanek, Annarosa Leri, Jan Kajstura, Federico Quaini, Giordano Tasca, Daniele Torella, Clotilde Castaldo, Bernardo Nadalginard, Eugenio Quaini, Piero AnversaAbstract:Abstract It is generally believed that increase in adult contractile cardiac mass can be accomplished only by hypertrophy of existing Myocytes. Documentation of myocardial regeneration in acute stress has challenged this dogma and led to the proposition that Myocyte renewal is fundamental to cardiac homeostasis. Here we report that in human aortic stenosis, increased cardiac mass results from a combination of Myocyte hypertrophy and hyperplasia. Intense new Myocyte formation results from the differentiation of stem-like cells committed to the Myocyte lineage. These cells express stem cell markers and telomerase. Their number increased >13-fold in aortic stenosis. The finding of cell clusters with stem cells making the transition to cardiogenic and Myocyte precursors, as well as very primitive Myocytes that turn into terminally differentiated Myocytes, provides a link between cardiac stem cells and Myocyte differentiation. Growth and differentiation of these primitive cells was markedly enhanced in hypertrophy, consistent with activation of a restricted number of stem cells that, through symmetrical cell division, generate asynchronously differentiating progeny. These clusters strongly support the existence of cardiac stem cells that amplify and commit to the Myocyte lineage in response to increased workload. Their presence is consistent with the notion that Myocyte hyperplasia significantly contributes to cardiac hypertrophy and accounts for the subpopulation of cycling Myocytes.
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Myocyte death growth and regeneration in cardiac hypertrophy and failure
Circulation Research, 2003Co-Authors: Bernardo Nadalginard, Annarosa Leri, Jan Kajstura, Piero AnversaAbstract:The accepted paradigm considers the adult mammalian heart as a postmitotic organ, which possesses a relatively constant number of Myocytes from shortly after birth to adulthood and senescence. This notion is questioned by the demonstration that although most adult Myocytes are terminally differentiated, there is a small and continuously renewed subpopulation of cycling Myocytes produced by the differentiation of cardiac stem-like cells. Myocyte death and Myocyte regeneration are introduced as major determinants of cardiac homeostasis and alterations of ventricular anatomy and function in physiological and pathological states. The possibility of reconstituting dead myocardium by stem-like cells is advanced and proposed as a major area of future research.
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Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation
EMBO Journal, 2003Co-Authors: Annarosa Leri, Antonella Zacheo, Laura Barlucchi, Stefano Chimenti, Federica Limana, Sonia Franco, Bernardo Nadal-ginard, Jan Kajstura, Piero Anversa, Maria A BlascoAbstract:Cardiac failure is a frequent cause of death in the aging human population. Telomere attrition occurs with age, and is proposed to be causal for the aging process. To determine whether telomere shortening leads to a cardiac phenotype, we studied heart function in the telomerase knockout mouse, Terc-/-. We studied Terc-/- mice at the second, G2, and fifth, G5, generation. Telomere shortening in G2 and G5 Terc-/- mice was coupled with attenuation in cardiac Myocyte proliferation, increased apoptosis and cardiac Myocyte hypertrophy. On a single-cell basis, telomere shortening was coincidental with increased expression of p53, indicating the presence of dysfunctional telomeres in cardiac Myocytes from G5 Terc-/- mice. The impairment in cell division, the enhanced cardiac Myocyte death and cellular hypertrophy, are concomitant with ventricular dilation, thinning of the wall and cardiac dysfunction. Thus, inhibition of cardiac Myocyte replication provoked by telomere shortening, results in de-compensated eccentric hypertrophy and heart failure in mice. Telomere shortening with age could also contribute to cardiac failure in humans, opening the possibility for new therapies.
-
Myocyte proliferation and ventricular remodeling
Journal of Cardiac Failure, 2002Co-Authors: Annarosa Leri, Jan Kajstura, Piero AnversaAbstract:Improvement in the methodological approach to the analysis of the myocardium has provided clear evidence of cardiac Myocyte proliferation, questioning the general belief that the growth of the adult heart under physiological and pathological conditions can occur only by cellular hypertrophy. Myocyte regeneration contributes via Myocyte death to the physiological turnover of Myocytes and via Myocyte hypertrophy to cardiac remodeling. Several questions, however, remain to be answered. Among them, it is still unknown whether Myocyte multiplication exerts a positive and/or negative effect on ventricular anatomy and cardiac function. The addition of newly generated Myocytes leads to cavitary dilation with relative thinning of the wall. Conversely, Myocyte proliferation, characterized by the parallel addition of cells, can be expected to increase wall thickness, decrease chamber size, and ameliorate cardiac performance.
Kevin Kit Parker - One of the best experts on this subject based on the ideXlab platform.
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mechanotransduction the role of mechanical stress Myocyte shape and cytoskeletal architecture on cardiac function
Pflügers Archiv: European Journal of Physiology, 2011Co-Authors: Megan L Mccain, Kevin Kit ParkerAbstract:Mechanotransduction refers to the conversion of mechanical forces into biochemical or electrical signals that initiate structural and functional remodeling in cells and tissues. The heart is a kinetic organ whose form changes considerably during development and disease, requiring cardiac Myocytes to be mechanically durable and capable of fusing a variety of environmental signals on different time scales. During physiological growth, Myocytes adaptively remodel to mechanical loads. Pathological stimuli can induce maladaptive remodeling. In both of these conditions, the cytoskeleton plays a pivotal role in both sensing mechanical stress and mediating structural remodeling and functional responses within the Myocyte.
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sarcomere alignment is regulated by Myocyte shape
Cytoskeleton, 2008Co-Authors: Markanthony Bray, Sean P Sheehy, Kevin Kit ParkerAbstract:Cardiac organogenesis and pathogenesis are both characterized by changes in Myocyte shape, cytoskeletal architecture, and the extracellular matrix (ECM). However, the mechanisms by which the ECM influences Myocyte shape and myofibrillar patterning are unknown. We hypothesized that geometric cues in the ECM align sarcomeres by directing the actin network orientation. To test our hypothesis, we cultured neonatal rat ventricular Myocytes on islands of micro-patterned ECM to measure how they remodeled their cytoskeleton in response to extracellular cues. Myocytes spread and assumed the shape of circular and rectangular islands and reorganized their cytoskeletons and myofibrillar arrays with respect to the ECM boundary conditions. Circular Myocytes did not assemble predictable actin networks nor organized sarcomere arrays. In contrast, Myocytes cultured on rectangular ECM patterns with aspect ratios ranging from 1:1 to 7:1 aligned their sarcomeres in predictable and repeatable patterns based on highly localized focal adhesion complexes. Examination of averaged α-actinin images revealed invariant sarcomeric registration irrespective of Myocyte aspect ratio. Since the sarcomere subunits possess a fixed length, this observation indicates that cytoskeleton configuration is length-limited by the extracellular boundary conditions. These results indicate that modification of the extracellular microenvironment induces dynamic reconfiguring of the Myocyte shape and intracellular architecture. Furthermore, geometric boundaries such as corners induce localized myofibrillar anisotropy that becomes global as the Myocyte aspect ratio increases.
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Engineering design of a cardiac Myocyte
Journal of Computer-aided Materials Design, 2007Co-Authors: William J. Adams, Sean P Sheehy, Terrence Pong, Nicholas A. Geisse, B. Diop-frimpong, Kevin Kit ParkerAbstract:We describe a design algorithm to build a cardiac Myocyte with specific spatial dimensions and physiological function. Using a computational model of a cardiac muscle cell, we modeled calcium (Ca 2+ ) wave dynamics in a cardiac Myocyte withcontrolledspatialdimensions.ThemodeledMyocytewasreplicatedinvitrowhen primaryneonateratventricularMyocyteswereculturedonmicropatternedsubstrates. The Myocytes remodel to conform to the two dimensional boundary conditions and assume the shape of the printed extracellular matrix island. Mechanical perturbation of the Myocyte with an atomic force microscope results in calcium-induced calcium release from intracellular stores and the propagation of a Ca 2+ wave, as indicated by high speed video microscopy using fluorescent indicators of intracellular Ca 2+ .A nal- ysis and comparison of the measured wavefront dynamics with those simulated in the computer model reveal that the engineered Myocyte behaves as predicted by the model. These results are important because they represent the use of computer mod- eling, computer-aided design, and physiological experiments to design and validate the performance of engineered cells. The ability to successfully engineer biological cells and tissues for assays or therapeutic implants will require design algorithms and tools for quality and regulatory assurance.
Zhilin Qu - One of the best experts on this subject based on the ideXlab platform.
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Arrhythmogenic consequences of myofibroblast–Myocyte coupling
Cardiovascular Research, 2011Co-Authors: Thao P. Nguyen, Zhilin Qu, Alan Garfinkel, James N WeissAbstract:Aims Fibrosis is known to promote cardiac arrhythmias by disrupting myocardial structure. Given recent evidence that myofibroblasts form gap junctions with Myocytes at least in co-cultures, we investigated whether myofibroblast–Myocyte coupling can promote arrhythmia triggers, such as early afterdepolarizations (EADs), by directly influencing Myocyte electrophysiology. Methods and results Using the dynamic voltage clamp technique, patch-clamped adult rabbit ventricular Myocytes were electrotonically coupled to one or multiple virtual fibroblasts or myofibroblasts programmed with eight combinations of capacitance, membrane resistance, resting membrane potential, and gap junction coupling resistance, spanning physiologically realistic ranges. Myocytes were exposed to oxidative (1 mmol/L H2O2) or ionic (2.7 mmol/L hypokalaemia) stress to induce bradycardia-dependent EADs. In the absence of myofibroblast–Myocyte coupling, EADs developed during slow pacing (6 s), but were completely suppressed by faster pacing (1 s). However, in the presence of myofibroblast–Myocyte coupling, EADs could no longer be suppressed by rapid pacing, especially when myofibroblast resting membrane potential was depolarized (−25 mV). Analysis of the myofibroblast–Myocyte virtual gap junction currents revealed two components: an early transient-outward Ito-like current and a late sustained current. Selective elimination of the Ito-like component prevented EADs, whereas selective elimination of the late component did not. Conclusion Coupling of Myocytes to myofibroblasts promotes EAD formation as a result of a mismatch in early vs. late repolarization reserve caused by the Ito-like component of the gap junction current. These cellular and ionic mechanisms may contribute to the pro-arrhythmic risk in fibrotic hearts.
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effects of fibroblast Myocyte coupling on cardiac conduction and vulnerability to reentry a computational study
Heart Rhythm, 2009Co-Authors: Alan Garfinkel, Patrizia Camelliti, Peter Kohl, James N Weiss, Zhilin QuAbstract:BACKGROUND: Recent experimental studies have documented that functional gap junctions form between fibroblasts and Myocytes, raising the possibility that fibroblasts play roles in cardiac electrophysiology that extend beyond acting as passive electrical insulators. OBJECTIVE: The purpose of this study was to use computational models to investigate how fibroblasts may affect cardiac conduction and vulnerability to reentry under different fibroblast-Myocyte coupling conditions and tissue structures. METHODS: Computational models of two-dimensional tissue with fibroblast-Myocyte coupling were developed and numerically simulated. Myocytes were modeled by the phase I of the Luo-Rudy model, and fibroblasts were modeled by a passive model. RESULTS: Besides slowing conduction by cardioMyocyte decoupling and electrotonic loading, fibroblast coupling to Myocytes elevates Myocyte resting membrane potential, causing conduction velocity to first increase and then decrease as fibroblast content increases, until conduction failure occurs. Fibroblast-Myocyte coupling can also enhance conduction by connecting uncoupled Myocytes. These competing effects of fibroblasts on conduction give rise to different conduction patterns under different fibroblast-Myocyte coupling conditions and tissue structures. Elevation of Myocyte resting potential due to fibroblast-Myocyte coupling slows sodium channel recovery, which extends postrepolarization refractoriness. Owing to this prolongation of the Myocyte refractory period, reentry was more readily induced by a premature stimulation in heterogeneous tissue models when fibroblasts were electrotonically coupled to Myocytes compared with uncoupled fibroblasts acting as pure passive electrical insulators. CONCLUSIONS: Fibroblasts affect cardiac conduction by acting as obstacles or by creating electrotonic loading and elevating Myocyte resting potential. Functional fibroblast-Myocyte coupling prolongs the Myocyte refractory period, which may facilitate induction of reentry in cardiac tissue with fibrosis.
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Effects of fibroblast-Myocyte coupling on cardiac conduction and vulnerability to reentry: A computational study
Heart Rhythm, 2009Co-Authors: Yuanfang Xie, Patrizia Camelliti, Peter Kohl, James N Weiss, Alan Garfinkel, Zhilin QuAbstract:Background: Recent experimental studies have documented that functional gap junctions form between fibroblasts and Myocytes, raising the possibility that fibroblasts play roles in cardiac electrophysiology that extend beyond acting as passive electrical insulators. Objective: The purpose of this study was to use computational models to investigate how fibroblasts may affect cardiac conduction and vulnerability to reentry under different fibroblast-Myocyte coupling conditions and tissue structures. Methods: Computational models of two-dimensional tissue with fibroblast-Myocyte coupling were developed and numerically simulated. Myocytes were modeled by the phase I of the Luo-Rudy model, and fibroblasts were modeled by a passive model. Results: Besides slowing conduction by cardioMyocyte decoupling and electrotonic loading, fibroblast coupling to Myocytes elevates Myocyte resting membrane potential, causing conduction velocity to first increase and then decrease as fibroblast content increases, until conduction failure occurs. Fibroblast-Myocyte coupling can also enhance conduction by connecting uncoupled Myocytes. These competing effects of fibroblasts on conduction give rise to different conduction patterns under different fibroblast-Myocyte coupling conditions and tissue structures. Elevation of Myocyte resting potential due to fibroblast-Myocyte coupling slows sodium channel recovery, which extends postrepolarization refractoriness. Owing to this prolongation of the Myocyte refractory period, reentry was more readily induced by a premature stimulation in heterogeneous tissue models when fibroblasts were electrotonically coupled to Myocytes compared with uncoupled fibroblasts acting as pure passive electrical insulators. Conclusions: Fibroblasts affect cardiac conduction by acting as obstacles or by creating electrotonic loading and elevating Myocyte resting potential. Functional fibroblast-Myocyte coupling prolongs the Myocyte refractory period, which may facilitate induction of reentry in cardiac tissue with fibrosis. © 2009 Heart Rhythm Society.
