Enhanced Fibroblast–Myocyte Interactions in Response to Cardiac Injury

Vásquez, Carolina; Mohandas, Poornima; Louie, Karen L.; Benamer, Najate; Bapat, Ashwini; Morley, Gregory E.

doi:10.1161/circresaha.110.227421

Cited by 152 publications

(167 citation statements)

References 48 publications

(56 reference statements)

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“…35,36 Functionally, TGF-β 1 caused a several-fold increase of gap junctional coupling between myofibroblasts and cardiomyocytes in this study. Whereas coupling of myofibroblast-cardiomyocyte cell pairs was modest in absence of TGF-β 1 signaling (≈6% of cardiomyocyte-cardiomyocyte coupling values), this value increased to ≈33% after TGF-β 1 stimulation.…”

Section: Effects Of Tgf-β 1 On Myofibroblast Electrophysiology and Hesupporting

confidence: 49%

TGF-β ₁ (Transforming Growth Factor-β ₁ ) Plays a Pivotal Role in Cardiac Myofibroblast Arrhythmogenicity

Salvarani

Maguy

Simone

et al. 2017

Circ: Arrhythmia and Electrophysiology

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Background-TGF-β 1 (transforming growth factor-β 1 ) importantly contributes to cardiac fibrosis by controlling differentiation, migration, and collagen secretion of cardiac myofibroblasts. It is still elusive, however, to which extent TGF-β 1 alters the electrophysiological phenotype of myofibroblasts and cardiomyocytes and whether it affects proarrhythmic myofibroblast-cardiomyocyte crosstalk observed in vitro. Methods and Results-Patch-clamp recordings of cultured neonatal rat ventricular myofibroblasts revealed that TGF-β 1 , applied for 24 to 48 hours at clinically relevant concentrations (≤2.5 ng/mL), causes substantial membrane depolarization concomitant with a several-fold increase of transmembrane currents. Transcriptome analysis revealed TGF-β 1 -dependent changes in 29 of 63 ion channel/pump/connexin transcripts, indicating a pleiotropic effect on the electrical phenotype of myofibroblasts. Whereas not affecting cardiomyocyte membrane potentials and cardiomyocyte-cardiomyocyte gap junctional coupling, TGF-β 1 depolarized cardiomyocytes coupled to myofibroblasts by ≈20 mV and increased gap junctional coupling between myofibroblasts and cardiomyocytes >5-fold as reflected by elevated connexin 43 and consortin transcripts. TGF-β 1 -dependent cardiomyocyte depolarization resulted from electrotonic crosstalk with myofibroblasts as demonstrated by immediate normalization of cardiomyocyte electrophysiology after targeted disruption of coupled myofibroblasts and by cessation of ectopic activity of cardiomyocytes coupled to myofibroblasts during pharmacological gap junctional uncoupling. In cardiac fibrosis models exhibiting slow conduction and ectopic activity, block of TGF-β 1 signaling completely abolished both arrhythmogenic conditions. Conclusions-TGF-β 1 profoundly alters the electrophysiological phenotype of cardiac myofibroblasts. Apart from possibly contributing to the control of cell function in general, the changes proved to be pivotal for proarrhythmic myofibroblastcardiomyocyte crosstalk in vitro, which suggests that TGF-β 1 may play a potentially important role in arrhythmogenesis of the fibrotic heart. (Circ Arrhythm Electrophysiol. 2017;10:e004567.

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Section: Effects Of Tgf-β 1 On Myofibroblast Electrophysiology and Hesupporting

confidence: 49%

TGF-β ₁ (Transforming Growth Factor-β ₁ ) Plays a Pivotal Role in Cardiac Myofibroblast Arrhythmogenicity

Salvarani

Maguy

Simone

et al. 2017

Circ: Arrhythmia and Electrophysiology

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“…Fibroblasts can couple cardiomyocytes over extended distances, Fibroblast Ionic Remodeling and AF producing arrhythmogenic coupling delays (15). Cardiac injury promotes fibroblast-cardiomyocyte interactions, enhancing their ability to contribute to arrhythmia formation (32). Coculture of myofibroblasts with cardiomyocytes is associated with electrotonic coupling that is highly arrhythmogenic (18).…”

Section: Potential Role Of Fibroblast Electrical Remodeling In Atrialmentioning

confidence: 99%

Fibroblast Electrical Remodeling in Heart Failure and Potential Effects on Atrial Fibrillation

Aguilar

Huang

et al. 2014

Biophysical Journal

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Fibroblasts are activated in heart failure (HF) and produce fibrosis, which plays a role in maintaining atrial fibrillation (AF). The effect of HF on fibroblast ion currents and its potential role in AF are unknown. Here, we used a patch-clamp technique to investigate the effects of HF on atrial fibroblast ion currents, and mathematical computation to assess the potential impact of this remodeling on atrial electrophysiology and arrhythmogenesis. Atrial fibroblasts were isolated from control and tachypacing-induced HF dogs. Tetraethylammonium-sensitive voltage-gated fibroblast current (IKv,fb) was significantly downregulated (by ?44%), whereas the Ba(2+)-sensitive inward rectifier current (IKir,fb) was upregulated by 79%, in HF animals versus controls. The fibroblast resting membrane potential was hyperpolarized (?53 ± 2 mV vs. ?42 ± 2 mV in controls) and the capacitance was increased (29.7 ± 2.2 pF vs. 17.8 ± 1.4 pF in controls) in HF. These experimental findings were implemented in a mathematical model that included cardiomyocyte-fibroblast electrical coupling. IKir,fb upregulation had a profibrillatory effect through shortening of the action potential duration and hyperpolarization of the cardiomyocyte resting membrane potential. IKv,fb downregulation had the opposite electrophysiological effects and was antifibrillatory. Simulated pharmacological blockade of IKv,fb successfully terminated reentry under otherwise profibrillatory conditions. We conclude that HF induces fibroblast ion-current remodeling with IKv,fb downregulation and IKir,fb upregulation, and that, assuming cardiomyocyte-fibroblast electrical coupling, this remodeling has a potentially important effect on atrial electrophysiology and arrhythmogenesis, with the overall response depending on the balance of pro- and antifibrillatory contributions. These findings suggest that fibroblast K(+)-current remodeling is a novel component of AF-related remodeling that might contribute to arrhythmia dynamics.

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“…23 In our selected population of patients with symptomatic AF and enlarged atria undergoing thoracoscopic surgery for AF, no myofibroblasts were detected in the LAAs. However, myofibroblasts might play a more prominent role in other, more acute, causes of AF (eg, valvular AF, AF after ischemia, and experimental models) 24,25 or in the earlier phases of AF.…”

Section: The Role Of Myofibroblasts In the Substrate Of Afmentioning

confidence: 77%

Atrial Fibrosis and Conduction Slowing in the Left Atrial Appendage of Patients Undergoing Thoracoscopic Surgical Pulmonary Vein Isolation for Atrial Fibrillation

Gründeman

Berger

Smit

et al. 2015

Circ: Arrhythmia and Electrophysiology

105

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Background— Atrial fibrosis is an important component of the arrhythmogenic substrate in patients with atrial fibrillation (AF). We studied the effect of interstitial fibrosis on conduction velocity (CV) in the left atrial appendage of patients with AF. Methods and Results— Thirty-five left atrial appendages were obtained during AF surgery. Preparations were superfused and stimulated at 100 beats per minute. Activation was recorded with optical mapping. Longitudinal CV (CV L ), transverse CV (CV T ), and activation times (>2 mm distance) were measured. Interstitial collagen was quantified and graded qualitatively. The presence of fibroblasts and myofibroblasts was assessed immunohistochemically. Mean CV L was 0.55±0.22 m/s, mean CV T was 0.25±0.15 m/s, and the mean activation time was 9.31±5.45 ms. The amount of fibrosis was unrelated to CV or patient characteristics. CV L was higher in left atrial appendages with thick compared with thin interstitial collagen strands (0.77±0.22 versus 0.48±0.19 m/s; P =0.012), which were more frequently present in persistent patients with AF. CV T was not significantly different ( P =0.47), but activation time was 14.93±4.12 versus 7.95±4.12 ms in patients with thick versus thin interstitial collagen strands, respectively ( P =0.004). Fibroblasts were abundantly present and were associated with the presence of thick interstitial collagen strands ( P =0.008). Myofibroblasts were not detected in the left atrial appendage. Conclusions— In patients with AF, thick interstitial collagen strands are associated with higher CV L and increased activation time. Our observations demonstrate that the severity and structure of local interstitial fibrosis is associated with atrial conduction abnormalities, presenting an arrhythmogenic substrate for atrial re-entry.

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Enhanced Fibroblast–Myocyte Interactions in Response to Cardiac Injury

Cited by 152 publications

References 48 publications

TGF-β ₁ (Transforming Growth Factor-β ₁ ) Plays a Pivotal Role in Cardiac Myofibroblast Arrhythmogenicity

TGF-β ₁ (Transforming Growth Factor-β ₁ ) Plays a Pivotal Role in Cardiac Myofibroblast Arrhythmogenicity

Fibroblast Electrical Remodeling in Heart Failure and Potential Effects on Atrial Fibrillation

Atrial Fibrosis and Conduction Slowing in the Left Atrial Appendage of Patients Undergoing Thoracoscopic Surgical Pulmonary Vein Isolation for Atrial Fibrillation

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Enhanced Fibroblast–Myocyte Interactions in Response to Cardiac Injury

Cited by 152 publications

References 48 publications

TGF-β 1 (Transforming Growth Factor-β 1 ) Plays a Pivotal Role in Cardiac Myofibroblast Arrhythmogenicity

TGF-β 1 (Transforming Growth Factor-β 1 ) Plays a Pivotal Role in Cardiac Myofibroblast Arrhythmogenicity

Fibroblast Electrical Remodeling in Heart Failure and Potential Effects on Atrial Fibrillation

Atrial Fibrosis and Conduction Slowing in the Left Atrial Appendage of Patients Undergoing Thoracoscopic Surgical Pulmonary Vein Isolation for Atrial Fibrillation

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TGF-β ₁ (Transforming Growth Factor-β ₁ ) Plays a Pivotal Role in Cardiac Myofibroblast Arrhythmogenicity

TGF-β ₁ (Transforming Growth Factor-β ₁ ) Plays a Pivotal Role in Cardiac Myofibroblast Arrhythmogenicity