The electrical restitution of the non-propagated cardiac ventricular action potential

: Sudden changes in pacing cycle length are frequently associated with repolarization abnormalities initiating cardiac arrhythmias, and physiologists have long been interested in measuring the likelihood of these events before their manifestation. A marker of repolarization stability has been found in the electrical restitution (ER), the response of the ventricular action potential duration to a pre- or post-mature stimulation, graphically represented by the so-called ER curve. According to the restitution hypothesis (ERH), the slope of this curve provides a quantitative discrimination between stable repolarization and proneness to arrhythmias. ER has been studied at the body surface, whole organ, and tissue level, and ERH has soon become a key reference point in theoretical, clinical, and pharmacological studies concerning arrhythmia development, and, despite criticisms, it is still widely adopted. The ionic mechanism of ER and cellular applications of ERH are covered in the present review. The main criticism on ERH concerns its dependence from the way ER is measured. Over the years, in fact, several different experimental protocols have been established to measure ER, which are also described in this article. In reviewing the state-of-the art on cardiac cellular ER, I have introduced a notation specifying protocols and graphical representations, with the aim of unifying a sometime confusing nomenclature, and providing a physiological tool, better defined in its scope and limitations, to meet the growing expectations of clinical and pharmacological research

Spontaneous electrical activity of guinea-pig sinoatrial cells under modulation of two different pacemaker mechanisms

The main cellular determinants of cardiac automaticity are the hyperpolarization-activated cationic current If, and the electrogenic Na+/Ca2+ exchanger which generates an inward current after each action potential (AP). Our goal was to evaluate their relative role in pacemaking, by means of application of Ivabradine (IVA) (specific If blocker) and Ryanodine (RYA) (known to abolish calcium transient) on enzimatically isolated guinea-pig pacemaker cells. Spontaneous APs were recorded in patch-clamp whole cell configuration at 36°C from 7 cells perfused with the following sequence of solutions: physiological normal tyrode (NT), IVA 3 mM, NT and RYA 3 mM. Cycle length (CL, ms) and diastolic depolarization rate (DDR, V/s) were also calculated. Both blockers displayed similar effects, increasing CL (by 27 and 30%, respectively), and decreasing DDR (by 34 and 42%) with respect to NT exposure. These results suggest that both mechanisms are involved into pacemaking mechanism at a similar degree

IL METODO SCIENTIFICO NELLE SCIENZE DELLA NATURA, UN'APPLICAZIONE ALLA FISIOLOGIA: Scoperta e riscoperta della eccitabilità elettrica animale.

Gli animali, ma potremmo estendere la considerazione a tutti i viventi, sono dotati della proprietà fondamentale di rispondere a stimoli di diversa natura provenienti dall’ambiente interno a essi o da quello esterno con impulsi elettrici singoli o ripetuti, risposte che stanno alla base delle loro principali funzioni. Che si tratti di un paramecio che, urtata una foglia, cambia direzione di nuoto, di un’alga filamentosa che, beccata da un’anatra, induce la gelificazione del citoplasma per evitarne la perdita, di motoneuroni che attivano i muscoli della palpebra e mi fanno «schiacciare l’occhio», o di una cellula del nervo uditivo, attivata da una cellula cigliata dell’orecchio interno, che vibra al suono del violino di mia figlia, in tutti i casi una forma di energia è trasdotta, a livello cellulare, in un evento elettrico transitorio. Per la verità esistono anche cellule che si sono specializzate a emettere impulsi elettrici ripetuti spontaneamente, anche se non stimolate, e a costituire quindi dei veri e propri orologi interni all’organismo, essendo la loro frequenza di emissione costante in condizioni fisiologiche. Sono le cosiddette cellule pacemaker che sganciano, per così dire, il tempo scandito per le loro funzioni, dagli orologi biologici che battono coi giorni, le stagioni, gli astri. Che alla base della attività motoria e nervosa animale vi fossero fenomeni elettrici era già noto agli studiosi della seconda metà del XVIII secolo. Fino ad allora, una prestigiosa scuola di fisiologi, primo fra tutti Albrecht Von Haller (1708-1777) dell’Università di Berna, insieme con Leopoldo Caldani (1725- 1813) dell’Università di Padova, riteneva che il meccanismo fosse riconducibile a una «irritabilità» latente nei tessuti animali, una sorta di energia potenziale che, in particolari condizioni, si liberava e generava movimento o impulsi nervosi [1]. In quel periodo cominciarono tuttavia a comparire, sui banconi di lavoro di anatomisti e fisiologi, curiosi apparecchi atti a generare carica elettrica e, letteralmente, a imbottigliarla in recipienti (le bottiglie di Leida) che la rendevano a lungo disponibile per la sperimentazione. Da qui in poi la scoperta, e, come vedremo, la riscoperta della attività elettrica animale nasceva e procedeva di pari passo con la scienza dell’elettrologia prima e, più tardi, dell’elettronica e dell’informatica. L’intreccio con la fisica e la tecnica dell’elettricità è quindi costitutivo dell’elettrofisiologia e tesse il filo conduttore di una storia scientifica, controversa al suo inizio, ma per certi versi unica ed affascinante. La rilettura di questa storia consente di far bene emergere il travaglio che accompagna il tentativo di utilizzare il metodo scientifico nella scienza della vita, intrinseca-mente complessa quest’ultima e meravigliosamente qualitativa. Come nel seguente brano, Loligo media di Jünger: «Mi comparve dinanzi trasformato in un piatto di anelli delicatamente rosolati nell’olio, presso i quali era posata la testa dalle dieci braccia simile alla chiusa fioritura di un giglio di mare o al frammento di una figuretta mitologica. Quel che subito avevo intuito si confermò: l’armonia segreta che si nasconde in tutte le qualità di un essere diveniva palese anche al senso del gusto, ed anche se avessi mangiato con gli occhi bendati mi sarebbe stato possibile collocare nel siste-ma zoologico, con sufficiente sicurezza, l’origine di quel boccone» (E. Jünger, Il cuore avventuroso)

A protocol combining current- and voltage-clamp provides a novel and useful three-dimensional representation of cardiac action potential

A compact three-dimensional representation of cardiac action potential (AP) properties in terms of current source is presented here. The experimental protocol used to obtain such representation is based on the measure of instantaneous current-voltage relationships during the course of the AP. The procedure, which combines current- and voltage-clamps on patch clamped cardiac myocytes, has been previously applied to real cells, and then extended to computer simulations with cellular ventricular AP models. The three-dimensional AP representation allows to easily estimate membrane resistance during repolarization, a key factor for the modulation of ventricular repolarization. It also shows that, during late ventricular repolarization, membrane conductance becomes negative, i.e. repolarization is auto-regenerative. The novel AP representation is therefore a useful tool for both in vivo and in silico cardiac cellular electrophysiological investigations

Titanium dioxide nanoparticles promote arrhythmias via a direct interaction with rat cardiac tissue

BackgroundIn light of recent developments in nanotechnologies, interest is growing to better comprehend the interaction of nanoparticles with body tissues, in particular within the cardiovascular system. Attention has recently focused on the link between environmental pollution and cardiovascular diseases. Nanoparticles <50 nm in size are known to pass the alveolar¿pulmonary barrier, enter into bloodstream and induce inflammation, but the direct pathogenic mechanisms still need to be evaluated. We thus focused our attention on titanium dioxide (TiO2) nanoparticles, the most diffuse nanomaterial in polluted environments and one generally considered inert for the human body.MethodsWe conducted functional studies on isolated adult rat cardiomyocytes exposed acutely in vitro to TiO2 and on healthy rats administered a single dose of 2 mg/Kg TiO2 NPs via the trachea. Transmission electron microscopy was used to verify the actual presence of TiO2 nanoparticles within cardiac tissue, toxicological assays were used to assess lipid peroxidation and DNA tissue damage, and an in silico method was used to model the effect on action potential.ResultsVentricular myocytes exposed in vitro to TiO2 had significantly reduced action potential duration, impairment of sarcomere shortening and decreased stability of resting membrane potential. In vivo, a single intra-tracheal administration of saline solution containing TiO2 nanoparticles increased cardiac conduction velocity and tissue excitability, resulting in an enhanced propensity for inducible arrhythmias. Computational modeling of ventricular action potential indicated that a membrane leakage could account for the nanoparticle-induced effects measured on real cardiomyocytes.ConclusionsAcute exposure to TiO2 nanoparticles acutely alters cardiac excitability and increases the likelihood of arrhythmic events

A Computational View of the Historical Controversy on Animal Electricity

A scientific controversy retains often some controversial sides after its fundamentals has well been explained. This is particularly true for the controversy that arose in Italy in the second half of the eighteen century between the anatomist Luigi Galvani, and the physicist Alessandro Volta, around the intrinsic nature of nerve and muscular function. The two scientists were providing, almost simultaneously from the University of Bologna and Pavia respectively, two quite different explanations for the property of muscles of being electrically excitable and contract as a consequence. Science seemed then to touch the very intrinsic mechanism of living processes. Despite the fact that one of the two explanations was explaining better than the other, the weaker mechanism won the battle at the time. The biophysical mechanism of nerve excitability has then been clarified in 1950 by Hodgkin and Huxley, who later won the Nobel prize for their work. They unequivocally showed that Galvani was right and Volta quite wrong. Only specialists though notice that the Galvani-Volta controversy is frequently still thought wrong in schools. In this brief essay I want to show how easy-to-handle computer models can unveil where the subtle source of the controversy was hidden, and how an interdisciplinary approach can help drawing light into the multiple aspects of this extraordinary story

Ventricular Repolarization and Calcium Transient Show Resonant Behavior under Oscillatory Pacing Rate

Cardiac EC coupling is triggered by rhythmic depolarizing current fronts originating from the sino-atrial node, and the way variability in rhythm is associated with variability in action potential duration (APD) and, in turn, in the variability of calcium transient amplitude (CTA) and contraction is a key determinant of beating stability. Sinusoidal-varying pacing rate is adopted here in order to establish whether APD and CTA oscillations, elicited in a human ventricular AP model (OR) under oscillatory pacing, are consistent with the dynamics of two coupled harmonic oscillators, e.g., a two-degree-of-freedom system of mass and springs (MS model). I show evidence that this is the case, and that the MS model, preliminarily fitted to OR behavior, retains key features of the physiological system, such as the dependence of APD and CTA oscillation amplitudes from average value and from beat-to-beat changes in pacing rate, and the phase relationship between them. The bi-directionality of coupling between APD and CTA makes it difficult to discriminate which one leads EC coupling dynamics under variable pacing. The MS model suggests that the calcium cycling, with its greater inertia chiefly determined by the SR calcium release, is the leading mechanism. I propose the present approach to also be relevant at the whole organ level, where the need of compact representations of electromechanical interaction, particularly in clinical practice, remains urgent