Ultrastructural and Functional Remodeling of the Coupling Between Ca
            <sup>2+</sup>
            Influx and Sarcoplasmic Reticulum Ca
            <sup>2+</sup>
            Release in Right Atrial Myocytes From Experimental Persistent Atrial Fibrillation

Lenaerts, Ilse; Bito, Virginie; Heinzel, Frank R.; Driesen, Ronald B.; Holemans, Patricia; D'hooge, Jan; Heidbüchel, Hein; Sipido, Karin R.; Willems, Rik

doi:10.1161/circresaha.109.206276

Cited by 157 publications

(229 citation statements)

References 38 publications

(37 reference statements)

Supporting

Mentioning

200

Contrasting

Order By: Relevance

“…This resulted in a maximum I Ca,L current density of 23 pA/pF, which matches the reported values of both Lenaerts et al [13] and Deroubaix et al [14]. These changes resulted in a species-specific sheep RAA AP that matches well with reported AP properties [13,14]. It was then assumed that the same ionic changes used to differentiate between different cell types of the canine atria would apply to the sheep atria.…”

Section: Developing Single-cell Modelssupporting

confidence: 83%

“…These single-cell models take into account the experimentally observed electrical heterogeneity of sheep atrial cells in the kinetics and current densities of their ion channels. The models were based on, and validated against, extant experimental data from sheep atrial cells from Lenaerts et al [13] and Deroubaix et al [14]. In the cases where no experimental data were available, cross-species modelling techniques were adopted using data from Burashnikov et al [15], Li et al [16], Ehrlich et al [17] and Ramirez et al [18] for canine atrial cells.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A novel computational sheep atria model for the study of atrial fibrillation

et al. 2013

View full text Add to dashboard Cite

One contribution of 25 to a Theme Issue 'The virtual physiological human: integrative approaches to computational biomedicine'. Sheep are often used as animal models for experimental studies into the underlying mechanisms of cardiac arrhythmias. Previous studies have shown that biophysically detailed computer models of the heart provide a powerful alternative to experimental animal models for underpinning such mechanisms. In this study, we have developed a family of mathematical models for the electrical action potentials of various sheep atrial cell types. The developed cell models were then incorporated into a three-dimensional anatomical model of the sheep atria, which was recently reconstructed and segmented based on anatomical features within different regions. This created a novel biophysically detailed computational model of the three-dimensional sheep atria. Using the model, we then investigated the mechanisms by which paroxysmal rapid focal activity in the pulmonary veins can transit to sustained atrial fibrillation. It was found that the anisotropic property of the atria arising from the fibre structure plays an important role in facilitating the development of fibrillatory atrial excitation waves, and the electrical heterogeneity plays an important role in its initiation.

show abstract

Section: Developing Single-cell Modelssupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

A novel computational sheep atria model for the study of atrial fibrillation

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Under physiological conditions, SR vesicles move dynamically throughout the cell, approaching or moving away from the myocyte sarcolemma. SR dysfunction is a major feature of cardiac diseases, and its underlying mechanisms have been intensively studied 23, 24, 25. Abnormal SR Ca 2+ release occurs in human cardiomyocytes isolated from patients with heart failure, regardless of etiology 26.…”

Section: Discussionmentioning

confidence: 99%

REEP5 (Receptor Accessory Protein 5) Acts as a Sarcoplasmic Reticulum Membrane Sculptor to Modulate Cardiac Function

Yao

Xie

et al. 2018

JAHA

View full text Add to dashboard Cite

BackgroundHeart failure is a complex syndrome characterized by cardiac contractile impairment with high mortality. Defective intracellular Ca2+ homeostasis is the central cause under this scenario and tightly links to ultrastructural rearrangements of sarcolemmal transverse tubules and the sarcoplasmic reticulum (SR); however, the modulators of the SR architecture remain unknown. The SR has been thought to be a specialized endoplasmic reticulum membrane system. Receptor accessory proteins (REEPs)/DP1/Yop1p are responsible for shaping high‐curvature endoplasmic reticulum tubules. This study aimed to determine the role of REEPs in SR membrane shaping and thus cardiac function.Methods and ResultsWe identified REEP5 (receptor accessory protein 5) as more highly expressed than other REEP members in adult rat ventricular myocardium, and it was downregulated in the failing hearts. Targeted inactivation of REEP5 in rats specially deformed the cardiac SR membrane without affecting transverse tubules, and this was visualized by focused ion beam scanning electron microscopy–based 3‐dimensional reconstruction. Accordingly, simultaneous recordings of depolarization‐induced Ca2+ currents and Ca2+ transients in REEP5‐null cardiomyocytes revealed normal L‐type Ca2+ channel currents but a depressed SR Ca2+ release. Consequently, the excitation–contraction coupling gain of cardiomyocytes and consequent cardiac contractility were compromised. REEP5 deficiency did not alter the expression of major proteins involved in Ca2+ handling in the heart.Conclusions REEP5 modulates cardiac function by shaping the SR. REEP5 defect deforms the SR architecture to depress cardiac contractility. REEP5‐dependent SR shaping might have potential as a therapeutic target for heart failure.

show abstract

“…These findings, in combination with diffusional limitations in TATS's lumen (3,8), raise the possibility that AP may differ among membrane domains. Further interest in the TATS AP stems from the recent finding of loss and disorganization of tubules in several pathological conditions, including heart failure (9)(10)(11)(12)(13)(14). Because correlation between morphological TATS alterations and Ca 2+ -release asynchronicity has been observed (14,15), recording AP propagation in TATS can elucidate the fundamental electrophysiological mechanism linking structural and functional anomalies.…”

mentioning

confidence: 99%

Action potential propagation in transverse-axial tubular system is impaired in heart failure

Sacconi

Ferrantini

Lotti

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

123

View full text Add to dashboard Cite

The plasma membrane of cardiac myocytes presents complex invaginations known as the transverse-axial tubular system (TATS). Despite TATS's crucial role in excitation-contraction coupling and morphological alterations found in pathological settings, TATS's electrical activity has never been directly investigated in remodeled tubular networks. Here we develop an ultrafast random access multiphoton microscope that, in combination with a customly synthesized voltage-sensitive dye, is used to simultaneously measure action potentials (APs) at multiple sites within the sarcolemma with submillisecond temporal and submicrometer spatial resolution in real time. We find that the tight electrical coupling between different sarcolemmal domains is guaranteed only within an intact tubular system. In fact, acute detachment by osmotic shock of most tubules from the surface sarcolemma prevents AP propagation not only in the disconnected tubules, but also in some of the tubules that remain connected with the surface. This indicates that a structural disorganization of the tubular system worsens the electrical coupling between the TATS and the surface. The pathological implications of this finding are investigated in failing hearts. We find that AP propagation into the pathologically remodeled TATS frequently fails and may be followed by local spontaneous electrical activity. Our findings provide insight on the relationship between abnormal TATS and asynchronous calcium release, a major determinant of cardiac contractile dysfunction and arrhythmias.cardiac disease | nonlinear microscopy | voltage imaging | t tubules T he transverse-axial tubular system (TATS) is a complex network characterized by transverse (t tubules, TT) and longitudinal (axial tubules, AT) components running from one transverse tubule to the next (1-3). The TATS of a myocyte rapidly conducts depolarization of the surface sarcolemma (SS) to the core of the cardiomyocyte (4). The coupling between sarcolemmal Ca 2+ entry during an action potential (AP) and Ca 2+ release from sarcoplasmic reticulum (SR) promotes synchronous myofibril activation throughout the myocyte (5). Recent studies highlight that AP-relevant ion channels and transporters are expressed in TATS membrane with different densities and isoforms from those in SS (6, 7). These findings, in combination with diffusional limitations in TATS's lumen (3,8), raise the possibility that AP may differ among membrane domains. Further interest in the TATS AP stems from the recent finding of loss and disorganization of tubules in several pathological conditions, including heart failure (9-14). Because correlation between morphological TATS alterations and Ca 2+ -release asynchronicity has been observed (14, 15), recording AP propagation in TATS can elucidate the fundamental electrophysiological mechanism linking structural and functional anomalies.Although the uniformity of the AP across the whole sarcolemma has been mathematically (16) and experimentally (17) proved, a potential alteration of the AP propagation i...

show abstract

Ultrastructural and Functional Remodeling of the Coupling Between Ca ²⁺ Influx and Sarcoplasmic Reticulum Ca ²⁺ Release in Right Atrial Myocytes From Experimental Persistent Atrial Fibrillation

Cited by 157 publications

References 38 publications

A novel computational sheep atria model for the study of atrial fibrillation

A novel computational sheep atria model for the study of atrial fibrillation

REEP5 (Receptor Accessory Protein 5) Acts as a Sarcoplasmic Reticulum Membrane Sculptor to Modulate Cardiac Function

Action potential propagation in transverse-axial tubular system is impaired in heart failure

Contact Info

Product

Resources

About

Ultrastructural and Functional Remodeling of the Coupling Between Ca 2+ Influx and Sarcoplasmic Reticulum Ca 2+ Release in Right Atrial Myocytes From Experimental Persistent Atrial Fibrillation

Cited by 157 publications

References 38 publications

A novel computational sheep atria model for the study of atrial fibrillation

A novel computational sheep atria model for the study of atrial fibrillation

REEP5 (Receptor Accessory Protein 5) Acts as a Sarcoplasmic Reticulum Membrane Sculptor to Modulate Cardiac Function

Action potential propagation in transverse-axial tubular system is impaired in heart failure

Contact Info

Product

Resources

About

Ultrastructural and Functional Remodeling of the Coupling Between Ca ²⁺ Influx and Sarcoplasmic Reticulum Ca ²⁺ Release in Right Atrial Myocytes From Experimental Persistent Atrial Fibrillation