Defects in T-tubular electrical activity underlie local alterations of calcium release in heart failure

Crocini, Claudia; Coppini, Raffaele; Ferrantini, Cecilia; Yan, Ping; Loew, Leslie M.; Tesi, Chiara; Cerbai, Elisabetta; Pavone, Francesco S.; Sacconi, Leonardo

doi:10.1073/pnas.1411557111

Cited by 77 publications

(123 citation statements)

References 40 publications

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“…Measurement of AP propagation in the TATS is a quite recent possibility, achieved by combining random access two-photon microscopy and voltage imaging (11,35). In line with the above considerations, this methodology revealed that the majority of T-tubules properly propagate the AP, even in diseased cardiomyocytes (11)(12)(13)(14). However, these results do not exclude the presence of individual electrically failing tubules.…”

Section: Discussionmentioning

confidence: 94%

“…Finally, in view of the formal analogy that exists between diffusion and electrical conduction, the apparent diffusion coefficient is linked to the effective electrical conductivity of the network. The methodology is first validated using an acutely detubulated cellular model (8,9) and then applied to assessing the effective electrical conductivity in diseased cardiomyocytes where structural (10) and functional (11)(12)(13)(14)(15) defects of the TATS have been described.…”

Section: Significancementioning

confidence: 99%

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Quantitative assessment of passive electrical properties of the cardiac T-tubular system by FRAP microscopy

Scardigli

Crocini

Ferrantini

et al. 2017

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

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Well-coordinated activation of all cardiomyocytes must occur on every heartbeat. At the cell level, a complex network of sarcolemmal invaginations, called the transverse-axial tubular system (TATS), propagates membrane potential changes to the cell core, ensuring synchronous and uniform excitation-contraction coupling. Although myocardial conduction of excitation has been widely described, the electrical properties of the TATS remain mostly unknown. Here, we exploit the formal analogy between diffusion and electrical conductivity to link the latter with the diffusional properties of TATS. Fluorescence recovery after photobleaching (FRAP) microscopy is used to probe the diffusion properties of TATS in isolated rat cardiomyocytes: A fluorescent dextran inside TATS lumen is photobleached, and signal recovery by diffusion of unbleached dextran from the extracellular space is monitored. We designed a mathematical model to correlate the time constant of fluorescence recovery with the apparent diffusion coefficient of the fluorescent molecules. Then, apparent diffusion is linked to electrical conductivity and used to evaluate the efficiency of the passive spread of membrane depolarization along TATS. The method is first validated in cells where most TATS elements are acutely detached by osmotic shock and then applied to probe TATS electrical conductivity in failing heart cells. We find that acute and pathological tubular remodeling significantly affect TATS electrical conductivity. This may explain the occurrence of defects in action potential propagation at the level of single T-tubules, recently observed in diseased cardiomyocytes.cardiac disease | transverse-axial tubular system | diffusion | electrical conductivity | porous rock T he sequential and coherent recruitment of all cardiomyocytes that occurs on every heartbeat is fundamental for proper contraction of the heart. Every heartbeat is triggered by a depolarizing event, the action potential (AP), spontaneously generated in cardiac pacemaker cells, which propagates through the conductive tissue and the working myocardium. The well-coordinated activation of all cardiomyocytes involves a spreading AP wave, conducted from cell to cell throughout the lattice of interconnections called gap junctions. The 3D electrical network of cardiomyocytes includes a finer order of complexity that involves a system of deep sarcolemmal membrane invaginations within each cell. As a network within a network, these sarcolemmal invaginations occur transversely with a periodicity roughly corresponding to that of sarcomere z-lines (transverse tubules, or T-tubules) and branch in the longitudinal direction (axial tubules) to form a complex system in atrial and ventricular cells, named the transverse-axial tubular system (TATS) (1, 2). The TATS allows membrane potential changes to propagate rapidly into the cardiomyocyte core and is considered an ultimate structural player for excitation-contraction coupling. During rapid depolarization, such as seen during the AP, Ca 2+ enters the cytos...

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Section: Discussionmentioning

confidence: 94%

Section: Significancementioning

confidence: 99%

Quantitative assessment of passive electrical properties of the cardiac T-tubular system by FRAP microscopy

Scardigli

Crocini

Ferrantini

et al. 2017

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

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“…This work has demonstrated, in myocytes from rats in which heart failure was induced by myocardial infarction, that there can be regions of apparently intact t-tubule that fail to propagate the action potential, resulting in delayed local Ca 2+ transient. Furthermore, in other t-tubular regions, spontaneous Ca 2+ release was found to trigger a local action potential (delayed after-depolarisation) that then, in turn, triggered a larger Ca 2+ release in the same region, indicating a role of t-tubules in arrhythmic events common in heart failure (Crocini et al 2014). To what extent these different mechanisms arising from t-tubule remodelling contribute to the development of heart failure remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

“…The t-tubules are an extension of the sarcolemma (Soeller and Cannell 1999) and provide a signalling pathway for the rapid propagation of the action potential deep within the myocyte interior, within milliseconds, facilitating a synchronous cell-wide Ca 2+ release that is much faster and larger than if the cell relied on Ca 2+ diffusion from initiation events at the cell surface (Kawai et al 1999;Cordeiro et al 2001;Brette et al 2002Brette et al , 2006Louch et al 2004;Sacconi et al 2012). For example, a typical Ca 2+ transient in rat myocytes with intact t-tubules reaches its peak Ca 2+ within ∼60 milliseconds; if the t-tubules are removed by osmotic shock-induced detubulation with formamide, peak Ca 2+ is reached much later, in ∼120 milliseconds (Crocini et al 2014). …”

Section: Introductionmentioning

confidence: 99%

Transverse tubule remodelling: a cellular pathology driven by both sides of the plasmalemma?

2017

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Transverse (t)-tubules are invaginations of the plasma membrane that form a complex network of ducts, 200-400 nm in diameter depending on the animal species, that penetrates deep within the cardiac myocyte, where they facilitate a fast and synchronous contraction across the entire cell volume. There is now a large body of evidence in animal models and humans demonstrating that pathological distortion of the t-tubule structure has a causative role in the loss of myocyte contractility that underpins many forms of heart failure. Investigations into the molecular mechanisms of pathological t-tubule remodelling to date have focused on proteins residing in the intracellular aspect of t-tubule membrane that form linkages between the membrane and myocyte cytoskeleton. In this review, we shed light on the mechanisms of ttubule remodelling which are not limited to the intracellular side. Our recent data have demonstrated that collagen is an integral part of the t-tubule network and that it increases within the tubules in heart failure, suggesting that a fibrotic mechanism could drive cardiac junctional remodelling. We examine the evidence that the linkages between the extracellular matrix, t-tubule membrane and cellular cytoskeleton should be considered as a whole when investigating the mechanisms of t-tubule pathology in the failing heart.

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“…Light provides the versatility required to develop and test customized stimulation patterns capable of successfully interrupting arrhythmias at much lower energy. We exploit recent advancements in optogenetics [6][7][8] and imaging techniques 9,10 to develop a novel optical platform capable of simultaneously mapping and controlling the electrical activity of whole hearts with sub-millisecond temporal resolution. An ultra-fast laser scanning system is used to design arbitrarily-chosen stimulation patterns across the whole heart.…”

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confidence: 99%

Optogenetics Design of Mechanistically-Based Stimulation Patterns for Cardiac Defibrillation

Crocini

Ferrantini

Coppini

et al. 2017

Biophysical Journal

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Current rescue therapies for life-threatening arrhythmias ignore the pathological electro-anatomical substrate and base their efficacy on a generalized electrical discharge. Here, we developed an all-optical platform to examine less invasive defibrillation strategies. An ultrafast wide-field macroscope was developed to optically map action potential propagation with a red-shifted voltage sensitive dye in whole mouse hearts. The macroscope was implemented with a random-access scanning head capable of drawing arbitrarily-chosen stimulation patterns with sub-millisecond temporal resolution allowing precise epicardial activation of Channelrhodopsin2 (ChR2). We employed this optical system in the setting of ventricular tachycardia to optimize mechanistic, multi-barrier cardioversion/defibrillation patterns. Multiple regions of conduction block were created with a very high cardioversion efficiency but with lower energy requirements as compared to whole ventricle interventions to interrupt arrhythmias. This work demonstrates that defibrillation energies can be substantially reduced by applying discrete stimulation patterns and promotes the progress of current anti-arrhythmic strategies.Life-threatening arrhythmias, including atrial and ventricular fibrillation, represent a social and economic burden in the general population. The electro-anatomical substrate of these arrhythmias is characterized by conduction heterogeneities that facilitate micro and macro re-entrant circuits 1 . Electrical cardioversion, attempted either with external or implantable devices, is the first choice option according to current guidelines 2 . However, electrical cardioversion operates ignoring the characteristic features of re-entrant conduction pathways and its efficacy rests on capturing the whole heart with a generalized electrical discharge 3 . For instance, implantable cardioverter defibrillator (ICD) shocks cause intense pain, myocardium damage, and chest muscle contractures, with a non-negligible risk of accidents and often unbearable psychological discomfort 4 ; moreover, inappropriate ICD-shocks are regrettably common 5 . In this scenario, efforts towards minimizing ICD's electrical entrainments require a deeper comprehension of the events leading to the onset and development of arrhythmias. Light provides the versatility required to develop and test customized stimulation patterns capable of successfully interrupting arrhythmias at much lower energy. We exploit recent advancements in optogenetics 6-8 and imaging techniques 9,10 to develop a novel optical platform capable of simultaneously mapping and controlling the electrical activity of whole hearts with sub-millisecond temporal resolution. An ultra-fast laser scanning system is used to design arbitrarily-chosen stimulation patterns across the whole heart. The platform is then used to characterize arrhythmias and to efficiently restore the cardiac sinus rhythm by intervening with customized stimulation patterns. ResultsA wide-field macroscope (Fig. 1a) operating at 2,000 frames...

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Defects in T-tubular electrical activity underlie local alterations of calcium release in heart failure

Cited by 77 publications

References 40 publications

Quantitative assessment of passive electrical properties of the cardiac T-tubular system by FRAP microscopy

Quantitative assessment of passive electrical properties of the cardiac T-tubular system by FRAP microscopy

Transverse tubule remodelling: a cellular pathology driven by both sides of the plasmalemma?

Optogenetics Design of Mechanistically-Based Stimulation Patterns for Cardiac Defibrillation

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