Complex electrophysiological remodeling in postinfarction ischemic heart failure

Hegyi, Bence; Bossuyt, Julie; Griffiths, Leigh G.; Shimkunas, Rafael; Coulibaly, Zana; Jian, Zhong; Grimsrud, Kristin N; Søndergaard, Claus S.; Ginsburg, Kenneth S.; Chiamvimonvat, Nipavan; Belardinelli, Luiz; Varró, András; Papp, Julius Gy.; Pollesello, Piero; Levijoki, Jouko; Izu, Leighton T.; Boyd, W. Douglas; Bányász, Tamás; Bers, Donald M.; Chen‐Izu, Ye

doi:10.1073/pnas.1718211115

Cited by 77 publications

(96 citation statements)

References 29 publications

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“…In spite of its relative importance, many aspects of I Na-late are still poorly understood. In contrast to the detailed data obtained in rabbit [18], guinea pig [19] and porcine [20] myocytes, we have only a limited number of recordings of native human and canine I Na-late , since these experiments were typically performed using conventional voltage clamp arrangements and many of them at room temperature [7,8,[21][22][23]. Self action potential voltage clamp measurements, delivering the cell's own AP as a command signal, are not available in the literature either for canine or human ventricular cardiomyocytes.…”

Section: Introductioncontrasting

confidence: 73%

“…Regarding undiseased human ventricular cells, this is the first report using the APVC technique. Our most important finding was to demonstrate that canine myocytes can be used as a reasonably good model to study human I Na-late -in contrast to myocytes originating from other mammals including guinea pigs, rabbits and pigs, since all in these latter species the current displays a crescendo profile [18][19][20]. Important implication of this interspecies difference is that the relative contribution of I Na-late to action potential morphology (with the concomitant Na + and Ca 2+ load resulting in increased arrhythmia propensity) increases with lengthening of APD in the "crescendo" group in contrast to the "decrescendo" situation, and vice versa, it will be relatively smaller at shorter APDs.…”

Section: Discussionmentioning

confidence: 99%

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Late sodium current in human, canine and guinea pig ventricular myocardium

Horváth

Hézsô

Szentandrássy

et al. 2020

Journal of Molecular and Cellular Cardiology

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Although late sodium current (I Na-late) has long been known to contribute to plateau formation of mammalian cardiac action potentials, lately it was considered as possible target for antiarrhythmic drugs. However, many aspects of this current are still poorly understood. The present work was designed to study the true profile of I Nalate in canine and guinea pig ventricular cells and compare them to I Na-late recorded in undiseased human hearts. I Na-late was defined as a tetrodotoxin-sensitive current, recorded under action potential voltage clamp conditions using either canonic-or self-action potentials as command signals. Under action potential voltage clamp conditions the amplitude of canine and human I Na-late monotonically decreased during the plateau (decrescendoprofile), in contrast to guinea pig, where its amplitude increased during the plateau (crescendo profile). The decrescendo-profile of canine I Na-late could not be converted to a crescendo-morphology by application of ramplike command voltages or command action potentials recorded from guinea pig cells. Conventional voltage clamp experiments revealed that the crescendo I Na-late profile in guinea pig was due to the slower decay of I Na-late in this species. When action potentials were recorded from multicellular ventricular preparations with sharp microelectrode, action potentials were shortened by tetrodotoxin, which effect was the largest in human, while smaller in canine, and the smallest in guinea pig preparations. It is concluded that important interspecies differences exist in the behavior of I Na-late. At present canine myocytes seem to represent the best model of human ventricular cells regarding the properties of I Na-late. These results should be taken into account when pharmacological studies with I Na-late are interpreted and extrapolated to human. Accordingly, canine ventricular tissues or myocytes are suggested for pharmacological studies with I Na-late inhibitors or modifiers. Incorporation of present data to human action potential models may yield a better understanding of the role of I Na-late in action potential morphology, arrhythmogenesis, and intracellular calcium dynamics. with physiological and pathological significance recognized long ago [1-3], its pathophysiological role in LQT3 [4] and heart failure [5-8] has been emphasized only in the last decades. I Na-late-as an inward current-contributes to plateau formation and is responsible for largely

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Section: Introductioncontrasting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Late sodium current in human, canine and guinea pig ventricular myocardium

Horváth

Hézsô

Szentandrássy

et al. 2020

Journal of Molecular and Cellular Cardiology

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“…; Hegyi et al . ). Perhaps a similar approach might be useful to determine how different MCET pathways stratify in time and force hierarchies.…”

Section: Perspectivesmentioning

confidence: 97%

“…strain, stress, location, magnitude) imposed on the myocyte and determine which MCET pathway is operative by pharmacological or genetic dissection. Sequential application of specific channel blockers enabled electrophysiologists to 'peel back' the layers of ionic currents that underlie the action potential (Banyasz et al 2011;Hegyi et al 2018). Perhaps a similar approach might be useful to determine how different MCET pathways stratify in time and force hierarchies.…”

Section: Plurality Of Mechano-chemo-electro-transduction Pathwaysmentioning

confidence: 99%

Mechano‐electric and mechano‐chemo‐transduction in cardiomyocytes

Izu

Kohl

Boyden

et al. 2020

The Journal of Physiology

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Cardiac excitation‐contraction (E‐C) coupling is influenced by (at least) three dynamic systems that couple and feedback to one another (see Abstract Figure). Here we review the mechanical effects on cardiomyocytes that include mechano‐electro‐transduction (commonly referred to as mechano‐electric coupling, MEC) and mechano‐chemo‐transduction (MCT) mechanisms at cell and molecular levels which couple to Ca2+‐electro and E‐C coupling reviewed elsewhere. These feedback loops from muscle contraction and mechano‐transduction to the Ca2+ homeodynamics and to the electrical excitation are essential for understanding the E‐C coupling dynamic system and arrhythmogenesis in mechanically loaded hearts. This white paper comprises two parts, each reflecting key aspects from the 2018 UC Davis symposium: MEC (how mechanical load influences electrical dynamics) and MCT (how mechanical load alters cell signalling and Ca2+ dynamics). Of course, such separation is artificial since Ca2+ dynamics profoundly affect ion channels and electrogenic transporters and vice versa. In time, these dynamic systems and their interactions must become fully integrated, and that should be a goal for a comprehensive understanding of how mechanical load influences cell signalling, Ca2+ homeodynamics and electrical dynamics. In this white paper we emphasize current understanding, consensus, controversies and the pressing issues for future investigations. Space constraints make it impossible to cover all relevant articles in the field, so we will focus on the topics discussed at the symposium.

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“…Experiments with isolated canine myocytes from the BZ 5 days after MI have shown that a decrease in repolarizing currents prolongs APD (10). However, recent experimental evidence has demonstrated that a shift in balance between inward and outward currents acts to shorten APD in the BZ while prolonging APD in remote zones (40). In contrast to the single-cell level, there is little compelling evidence for APD prolongation in the BZ of chronic infarct regions, particularly in the human ventricle (24).…”

Section: Arrhythmogenesis By Prolonged Apdmentioning

confidence: 99%

Factors Promoting Conduction Slowing as Substrates for Block and Reentry in Infarcted Hearts

Campos

Whitaker

Neji

et al. 2019

Biophysical Journal

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The development of effective and safe therapies for scar-related ventricular tachycardias requires a detailed understanding of the mechanisms underlying the conduction block that initiates electrical re-entries associated with these arrhythmias. Conduction block has been often associated with electrophysiological changes that prolong action potential duration (APD) within the border zone (BZ) of chronically infarcted hearts. However, experimental evidence suggests that remodeling processes promoting conduction slowing as opposed to APD prolongation mark the chronic phase. In this context, the substrate for the initial block at the mouth of an isthmus/diastolic channel leading to ventricular tachycardia is unclear. The goal of this study was to determine whether electrophysiological parameters associated with conduction slowing can cause block and reentry in the BZ. In silico experiments were conducted on two-dimensional idealized infarct tissue as well as on a cohort of postinfarction porcine left ventricular models constructed from ex vivo magnetic resonance imaging scans. Functional conduction slowing in the BZ was modeled by reducing sodium current density, whereas structural conduction slowing was represented by decreasing tissue conductivity and including fibrosis. The arrhythmogenic potential of APD prolongation was also tested as a basis for comparison. Within all models, the combination of reduced sodium current with structural remodeling more often degenerated into re-entry and, if so, was more likely to be sustained for more cycles. Although re-entries were also detected in experiments with prolonged APD, they were often not sustained because of the subsequent block caused by long-lasting repolarization. Functional and structural conditions associated with slow conduction rather than APD prolongation form a potent substrate for arrhythmogenesis at the isthmus/BZ of chronically infarcted hearts. Reduced excitability led to block while slow conduction shortened the wavelength of propagation, facilitating the sustenance of re-entries. These findings provide important insights for models of patient-specific risk stratification and therapy planning.

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Complex electrophysiological remodeling in postinfarction ischemic heart failure

Cited by 77 publications

References 29 publications

Late sodium current in human, canine and guinea pig ventricular myocardium

Late sodium current in human, canine and guinea pig ventricular myocardium

Mechano‐electric and mechano‐chemo‐transduction in cardiomyocytes

Factors Promoting Conduction Slowing as Substrates for Block and Reentry in Infarcted Hearts

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