Late Sodium Current Inhibition Reverses Electromechanical Dysfunction in Human Hypertrophic Cardiomyopathy

Coppini, Raffaele; Ferrantini, Cecilia; Yao, Lina; Fan, Peidong; Lungo, Martina Del; Stillitano, Francesca; Sartiani, Laura; Tosi, Benedetta; Suffredini, Silvia; Tesi, Chiara; Yacoub, Magdi H.; Olivotto, Iacopo; Belardinelli, Luiz; Cerbai, Elisabetta; Mugelli, Alessandro

doi:10.1161/circulationaha.112.134932

Cited by 358 publications

(580 citation statements)

References 54 publications

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“…value of approximately 3 µM, which results in near-zero isometric twitch tension based on calcium data measurements from Coppini et al, which have a peak value below 1 µM [9]. Thus, fitting isometric twitch data required differences in cooperativity and calcium sensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…The parameter sweep indicated that the parameter ν, which scales the unbound-to-weak transition rate k uw , could not be constrained based on twitch kinetics. Values of ν ∈ [4,12] all result in insignificant differences with d t ∈ [7,9], with no clear pattern of higher or lower ν consistently giving better fits. The next section describes the use of whole-organ simulations to determine this final parameter, resulting in our choice of ν = 7.…”

Section: Isometric Twitch Response In Intact Musclementioning

confidence: 97%

“…Combined force, length and calcium measurements from intact trabeculae have not been reported. Here we integrate observations of calcium transients and tension transients from different sources, to estimate the differences in parameters between skinned myocytes and intact tissue preparations The calcium transient we use as input is based on work by Coppini et al [9], which is shown in Figure 6. We use isometric twitch measurements from isolated left ventricular muscle strips [44,53] at body temperature, from which we derive our target ranges for a time to peak tension (TPT) of 147-172 ms, a time to 50% relaxation (RT 50 ) of 109-125 ms and a time to 95% relaxation (RT 95 ) of 291-377 ms.…”

Section: Isometric Twitch Response In Intact Musclementioning

confidence: 99%

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A model of cardiac contraction based on novel measurements of tension development in human cardiomyocytes

Land

Park-Holohan

Smith

et al. 2017

Journal of Molecular and Cellular Cardiology

110

147

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Experimental data from human cardiac myocytes at body temperature is crucial for a quantitative understanding of clinically relevant cardiac function and development of whole-organ computational models. However, such experimental data is currently very limited. Specifically, important measurements to characterize changes in tension development in human cardiomyocytes that occur with perturbations in cell length are not available. To address this deficiency, in this study we present an experimental data set collected from skinned human cardiac myocytes, including the passive and viscoelastic properties of isolated myocytes, the steady-state force calcium relationship at different sarcomere lengths, and changes in tension following a rapid increase or decrease in length, and after constant velocity shortening. This data set is, to our knowledge, the first characterization of length and velocity-dependence of tension generation in human skinned cardiac myocytes at body temperature.We use this data to develop a computational model of contraction and passive viscoelasticity in human myocytes. Our model includes troponin C kinetics, tropomyosin kinetics, a three-state crossbridge model that accounts for the distortion of crossbridges, and the cellular viscoelastic response. Each component is parametrized using our experimental data collected in human cardiomyocytes at body temperature. Furthermore we are able to confirm that properties of length-dependent activation at 37• C are similar to other species, with a shift in calcium sensitivity and increase in maximum tension. We revise our model of tension generation in the skinned isolated myocyte to replicate reported tension traces generated in intact muscle during isometric tension, to provide a model of human tension generation for multi-scale simulations. This process requires changes to calcium sensitivity, cooperativity, and crossbridge transition rates. We apply this model within multi-scale simulations of biventricular cardiac function and further refine the parametrization within the whole organ context, based on obtaining a healthy ejection fraction. This process reveals that crossbridge cycling rates differ between skinned myocytes and intact myocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Isometric Twitch Response In Intact Musclementioning

confidence: 97%

Section: Isometric Twitch Response In Intact Musclementioning

confidence: 99%

See 1 more Smart Citation

A model of cardiac contraction based on novel measurements of tension development in human cardiomyocytes

Land

Park-Holohan

Smith

et al. 2017

Journal of Molecular and Cellular Cardiology

110

147

View full text Add to dashboard Cite

show abstract

“…Regardless of the source of Ca 2þ accumulation inside the CMs, this effect is expected invariably to have relevant consequences in terms of the generation and propagation of electrical impulses. Indeed, an increase in intracellular calcium concentration is a common feature of several acquired or congenital cardiomyopathies: for the sake of comparison, a 40% increase in diastolic Ca 2þ levels was measured in CMs from patients with hypertrophic cardiomyopathy as compared with control cells (75). Such an increase is sufficient to predispose CMs to contractile dysfunction and the occurrence of arrhythmogenic mechanisms (74).…”

Section: Discussionmentioning

confidence: 99%

Biochemical and Electrophysiological Modification of Amyloid Transthyretin on Cardiomyocytes

Sartiani

Bucciantini

Spinelli

et al. 2016

Biophysical Journal

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Transthyretin (TTR) amyloidoses are familial or sporadic degenerative conditions that often feature heavy cardiac involvement. Presently, no effective pharmacological therapy for TTR amyloidoses is available, mostly due to a substantial lack of knowledge about both the molecular mechanisms of TTR aggregation in tissue and the ensuing functional and viability modifications that occur in aggregate-exposed cells. TTR amyloidoses are of particular interest regarding the relation between functional and viability impairment in aggregate-exposed excitable cells such as peripheral neurons and cardiomyocytes. In particular, the latter cells provide an opportunity to investigate in parallel the electrophysiological and biochemical modifications that take place when the cells are exposed for various lengths of time to variously aggregated wild-type TTR, a condition that characterizes senile systemic amyloidosis. In this study, we investigated biochemical and electrophysiological modifications in cardiomyocytes exposed to amyloid oligomers or fibrils of wild-type TTR or to its T4-stabilized form, which resists tetramer disassembly, misfolding, and aggregation. Amyloid TTR cytotoxicity results in mitochondrial potential modification, oxidative stress, deregulation of cytoplasmic Ca 2þ levels, and Ca 2þ cycling. The altered intracellular Ca 2þ cycling causes a prolongation of the action potential, as determined by whole-cell recordings of action potentials on isolated mouse ventricular myocytes, which may contribute to the development of cellular arrhythmias and conduction alterations often seen in patients with TTR amyloidosis. Our data add information about the biochemical, functional, and viability alterations that occur in cardiomyocytes exposed to aggregated TTR, and provide clues as to the molecular and physiological basis of heart dysfunction in sporadic senile systemic amyloidosis and familial amyloid cardiomyopathy forms of TTR amyloidoses.

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“…Recent studies indicate that CaMKII activation and I Na,L augmentation play important roles in the ROS-induced Ca 2+ overload and arrhythmias [4] . Under various cardiac pathological conditions, there exists a lethal cycle between CaMKII and I Na,L [30,31] . ROS dramatically enhances I Na,L via CaMKII activation; the enhanced I Na,L further activates CaMKII, leading to CaMKII over-activation [6,30] .…”

Section: Discussionmentioning

confidence: 99%

Resveratrol protects rabbit ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca2+ overload

Wang

Gao

et al. 2013

Acta Pharmacol Sin

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Aim: To investigate whether resveratrol suppressed oxidative stress-induced arrhythmogenic activity and Ca 2+ overload in ventricular myocytes and to explore the underlying mechanisms. Methods: Hydrogen peroxide (H 2 O 2 , 200 μmol/L)) was used to induce oxidative stress in rabbit ventricular myocytes. Cell shortening and calcium transients were simultaneously recorded to detect arrhythmogenic activity and to measure intracellular Ca 2+ ([Ca 2+ ] i ). Ca 2+ /calmodulin-dependent protein kinases II (CaMKII) activity was measured using a CaMKII kit or Western blotting analysis. Voltageactivated Na + and Ca 2+ currents were examined using whole-cell recording in myocytes. In addition, resveratrol markedly blunted H 2 O 2 -induced diastolic [Ca 2+ ] i accumulation and prevented the myocytes from developing hypercontracture. In whole-cell recording studies, H 2 O 2 significantly enhanced the late Na + current (I Na,L ) and L-type Ca 2+ current (I Ca,L ) in myocytes, which were dramatically suppressed or prevented by resveratrol. Furthermore, H 2 O 2 -induced ROS production and CaMKII activation were significantly prevented by resveratrol. Conclusion: Resveratrol protects ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca 2+ overload through inhibition of I Na,L /I Ca,L , reduction of ROS generation, and prevention of CaMKII activation.

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Late Sodium Current Inhibition Reverses Electromechanical Dysfunction in Human Hypertrophic Cardiomyopathy

Abstract: 2+ ihandling proteins changes identified, an enhanced I NaL seems to be a major contributor to the electrophysiological and Ca

Cited by 358 publications

References 54 publications

A model of cardiac contraction based on novel measurements of tension development in human cardiomyocytes

A model of cardiac contraction based on novel measurements of tension development in human cardiomyocytes

Biochemical and Electrophysiological Modification of Amyloid Transthyretin on Cardiomyocytes

Resveratrol protects rabbit ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca2+ overload

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