Physiological Laboratory và the Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom

Cardiac arrhythmias can follow disruption of the normal cellular electrophysiological processes underlying excitable activity và their tissue propagation as coherent wavefronts from the primary sinoatrial node pacemaker, through the atria, conducting structures and ventricular myocardium. These physiological events are driven by interacting, voltage-dependent, processes of activation, inactivation, & recovery in the ion channels present in cardiomyocyte membranes. Generation & conduction of these events are further modulated by intracellular Ca2+ homeostasis, & metabolic and structural change. This nhận xét describes experimental studies on murine models for known clinical arrhythmic conditions in which these mechanisms were modified by genetic, physiological, or pharmacological manipulation. These exemplars yielded molecular, physiological, and structural phenotypes often directly translatable lớn their corresponding clinical conditions, which could be investigated at the molecular, cellular, tissue, organ, & whole animal levels. Arrhythmogenesis could be explored during normal pacing activity, regular stimulation, following imposed extra-stimuli, or during progressively incremented steady pacing frequencies. Arrhythmic substrate was identified with temporal and spatial functional heterogeneities predisposing lớn reentrant excitation phenomemãng cầu. These could arise from abnormalities in cardiac pacing function, tissue electrical connectivity, và cellular excitation & recovery. Triggering events during or following recovery from action potential excitation could thereby lead to sustained arrhythmia. These surface membrane processes were modified by alterations in cellular Ca2+ homeostasis và energetics, as well as cellular & tissue structural change. Study of murine systems thus offers major insights into lớn both our understanding of normal cardiac activity & its propagation, và their relationship lớn mechanisms generating clinical arrhythmias.

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A. Scope of Review

Cardiac arrhythmias result from disruption of the orderly physiological sequence of electrical excitation processes that initiates coordinated and effective cardiac contraction. Of the wide clinical variety of arrhythmic variants, ventricular arrhythmias, particularly ventricular fibrillation (VF), often preceded by ventricular tachycardia (VT), potentially lead to lớn sudden cardiac death (SCD), defined as unexpected death from cardiac causes occurring 971, 1152). This major worldwide source of morbidity and mortality causes >300,000 & ∼70,000 deaths/year in the United States (USA) (535) và United Kingdom (UK) (215), respectively. Cardiac causes likely trương mục for 56.4% of nontraumatic, sudden death in autopsies of patients aged 5–35 years. Among these, arrhythmic causes likely account for ∼30% of cases. Although most of the latter cases result from ischemic heart disease (87), autopsy fails to lớn reveal a cause in ∼4% of SCD cases và 14% of all resuscitation attempts performed on patients aged 206, 738–740, 1149). Furthermore, such deaths often occur in the absence of structural abnormalities. This suggests the possibility of underlying channelopathy (116, 1122). Of deaths in infants 47), và 10–20% of these cases may result from channelopathy (575). Finally, arrhythmogenesis as a possible adverse effect of pharmacotherapeutic agents constitutes an important clinical problem with significant implications for pharmaceutical drug discovery (564).

Atrial arrhythmias are similarly becoming increasingly clinically và demographically important. Atrial fibrillation (AF) is the most comtháng sustained cardiac arrhythmia, with an overall prevalence of ∼1–2% of the general population (30, 683, 1093). AF is often associated with advancing age. It affects 4.7 & 9% of individuals of age >65 years & between 80 and 89 years, respectively (285, 1212). It predisposes khổng lồ further, major, cardiac & cerebrovascular morbidity and mortality (1093). Thus it increases risks of stroke fivefold (1268).

Sinus node disorder (SND) causes sinus bradycardia, sinus pause/arrest, chronotropic incompetence, & sinoatrial node (SAN) exit bloông xã (271). Its incidence increases exponentially with age to 1 in ∼600 cardiac patients aged >65 years. It is responsible for ∼1/2 of the million permanent pacemaker implants per year worldwide often in otherwise healthy individuals (272, 731).

Cardiac arrhythmogenesis poses significant clinical challenges in terms of both risk stratification and management (986). The latter are limited by our current inadequate understanding of the physiological mechanisms underlying initiation, maintenance, or propagation of cardiac arrhythmias, whether in the atria, ventricles, or the conducting tissues within or between them. Much valuable data have derived from human studies. However, much of this is inevitably observational. Physiological animal models of arrhythmic disease, whether involving pharmacological interventions or targeted genetic changes, permit more analytical studies of mechanisms và their consequences. Of these systems, transgenic mouse models are a relatively recent addition to other animal, rabbit, và canine systems. They offer a means of genetic & physiological manipulation that can be effectively directed at particular molecular targets strategic khổng lồ cardiac electrophysiological function.

This Review describes studies using some of these approaches, relating arrhythmic phenomemãng cầu to lớn cardiac electrophysiological properties. The latter in turn bear upon the generation of atrial or ventricular action potentials (APs), any abnormal, triggered activity accompanying such events, & associated metabolic and structural changes. The analysis is made in the light of the features of different exemplars modifying the activity of specific ion channels, cellular properties, or tissue or chamber structure. This involves first summarizing the roles of the major ion channels that underlie cardiac electrophysiological excitation, and the consequent excitation-contraction coupling processes involving the release và reuptake of sarcoplasmic reticular (SR) store Ca2+. Alterations in these processes are next related khổng lồ the properties of genetic murine exemplars of ion channel dysfunction. These include models for altered gap junction function compromising the spread of excitation, losses, and gains of function in the Na+, K+, và Ca2+ channels, & their subunits và associated proteins, affecting cell excitability, & ryanodine receptor (RyR2) modifications affecting cellular Ca2+ homeostasis. Finally, further upstream, metabolic, energetic, and structural changes are considered in relation to human arrhythmic conditions.

1. Ion current contributions khổng lồ cardiac action potentials

Effective cardiac function depends on repetitive sầu cycles of APhường excitation followed by recovery and the propagation of these events through the myocardial or conducting tissue as coherent electrical waves. This conduction takes place successively through the SAN, atria, atrioventricular bundles, Purkinje conducting tissue, & ventricular endocardial và epicardial myocardium. Repetitive atrial và ventricular excitation cycles normally depend on SAN automaticity driven by pacemaker cells (see sect. IIIA). The typical human ventricular APhường wavesize begins with a rapid (∼400 V/s) initial, phase 0, depolarization. This is driven by a rapidly increasing voltage-gated Na+ current (INa) (∼400 μA/μF). This drives the myocardial membrane potential from its normal negative sầu (approximately −90 mV) resting potential khổng lồ a positive sầu (+40 lớn +60 mV) voltage cthất bại khổng lồ the Na+ Nernst potential (Figure 1A and Table 1). This is followed by a, phase 1, initial rapid repolarization from this positive value that results from both inactivation of INa & the activation of fast và slow transient outward (Ito), K+, Ikhổng lồ,f, và Ikhổng lồ,s currents (Figure 1, B & C) (đánh giá in Refs. 71, 827, 863, 10trăng tròn, 1255).

Figure 1.Basic features of cardiac electrophysiological excitation. Inward (A) and outward (B) ionic current contributions attributable to surface membrane ion channels lớn human (C) and mouse (D) ventricular action potential (AP) waveforms.

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Table 1. Human and murine ventricular & atrial expression of cardiac ionic currents mediating excitable activity

HumanMouseCurrent/SymbolProteinGeneVentricleAtriumVentricleAtriumkích hoạt Potential Contribution
Voltage-gated inward currents
Fast Na+ current, INaNav1.5SCN5A++++++++++++<0>
L-type Ca2+ current, ICaL (dihydropyridine receptor: DHPR)Cav1.2CACNA1C+++++++++<2>
Voltage-gated outward currents
Fast transient outward K+ current, Ito,fKv4.2KCND2++++++++++<1>
Slow transient outward K+ current, Ito,s,Kv1.4KCNA4++++++++++<1>
Delayed rectifier K+ current, IKrKv11.1KCNH2 (HERG)++++++<3>
Delayed rectifier K+ current, IKs Kv7.1KCNQ1++++++<3>
4-Aminopyridine-sensitive sầu, rapidly activating, slowly inactivating K+ current, IKslow1Kv1.5KCNA5+++
4-Aminopyridine-insensitive sầu, rapidly activating, slowly inactivating K+ current, IKslow2Kv2.1KCNB1+++
Sustained 4-aminopyridine-sensitive delayed rectifier K+ current, IssKv1.5KCNA5+++
Atrial-specific 4-aminopyridine-sensitive sầu ultrarapid delayed rectifier K+ current, IKurKv1.5KCNA5++++
Inward rectifiers
Inwardly rectifying current, IK1Kir2.1KCNJ2++++++++++<3>, <4>
Acetylcholine-activated, K+ current, IKAChKir3.1KCNJ3++++++
ATP-sensitive sầu potassium channel, IKATPKir6.2KCNJ11++++++++
Leak currents
Two-pore domain name K+ leak current, IK2pK2p3.1KCNK3++++++++++
Ca2+-activated K+ currents, IKCaKCa2.x-KCNNx++++++
Exchange currents
Transient, inward, Na+-Ca2+ exchange current, ItiNCXSLC8A1++++++++

kích hoạt potential contributions (human ventricle): <0>, phase 0 rapid depolarization; <1>, phase 1 initial rapid repolarization; <2>, phase 2 plateau; <3>, phase 3 repolarization; <4>, phase 4 electrical diastole.

This partial recovery is then followed by a phase 2, plateau, phase brought about by the activation of Ca2+ current (ICaL) through voltage-gated L-type Ca2+ channels often termed dihydropyridine receptors (DHPRs), reflecting their pharmacological sensitivities (107, 131, 556, 1319).

The action potential is then terminated by a phase 3 repolarization. This returns the membrane to its resting potential. This is driven by outward currents mediated by a species-dependent variety of K+ channels. In human ventricles, these include the delayed rectifier IKr (1169) & IKs (1097), inwardly rectifying IK1 (693), và two-pore domain K+ leak currents (IK2p) (1020).

This culminates in full repolarization to electrical diastole (phase 4), in which the inward rectifying current IK1 plays a major part in maintaining a fully polarized (approximately −90 mV) resting potential. With repolarization, Nav1.5 channels recover their capacity for reexcitation. This recovery takes place over both absolute and relative sầu relative (effective) refractory periods (ERPs). Following this, Nav1.5 channels become capable of beginning the next excitation cycle.

Atrial APs begin from more depolarized resting potentials. The latter mainly reflects their smaller IK1. They show triangular waveforms with a more prominent phase 1 recovery reflecting a larger Ikhổng lồ. Atrial myocytes also specifically express ultrarapid delayed rectifier K+ (IKur) (1256), acetylcholine-activated K+ currents (IKACh), & Ca2+-activated K+ currents (IKCa) (1020, 1257). They show a less prominent phase 2 plateau phases than observed in ventricular APs. This is the consequence of smaller IKr, IKs, and IK1 currents but a more prolonged phase 3 repolarization (822).

Finally, ATP-sensitive K+ current (IKATP) occurs throughout the heart but generally accounts for relatively little current due to lớn its inhibition by intracellular ATP (3trăng tròn, 324). However, IKATP. may be activated under conditions of energetic áp lực (324, 419, 486, 1024).

2. Excitation-contraction coupling

Excitation-contraction coupling in ventricular myocytes is initiated by the surface membrane depolarization described above sầu and the transmission of this electrical change into lớn the transverse tubules. This results in an opening of voltage-gated L-type Ca2+ channels within the membranes of the transverse tubules, which then mediate the inward Ca2+ currents (ICaL) responsible for the phase 2 plateau phase of the APhường. The accompanying influx of extracellular Ca2+ produces a local elevation of cytosolic Ca2+ concentration (i) in regions of the sarcolemmal-SR junctions (107). This triggers an opening of cardiac SR RyR2 Ca2+ channels by a process of Ca2+-induced Ca2+ release (CICR) (298). The resulting release of intracellularly stored SR Ca2+ produces the elevation of i that drives the Ca2+-troponin binding which triggers mechanical activation. The cytosolic Ca2+-mediated regulation of cardiac, RyR2-Ca2+ release channel activity is facilitated by SR luminal Ca2+ (395, 622, 1069, 1285) and cytosolic ATPhường. It is inhibited by cytosolic Mg2+ (see sect. VIIA) (1313). RyR2 is also sensitive to thiol-oxidation & reactive sầu oxyren species (ROS) which may disrupt its intertên miền stability (see sect. VIIIA) (785). The CICR process in cardiac muscle contrasts with the control of RyR1 opening by the more rapid direct allosteric control by voltage-dependent configurational changes in the DHquảng bá in skeletal muscle. It explains the contrasting dependence and relative independence of these respective sầu excitation-contraction coupling processes upon extracellular (458, 462). It also contrasts with RyR2 function in inexcitable osteoclasts in which the RyR2 assumes a surface rather than an endoplasmic membrane site (460, 1314–1316).

The smaller atrial myocytes possess less prominent transverse tubular networks, particularly in hearts of small mammals such as the mouse. Their SR membranes are differentiated inkhổng lồ 1) corbular regions that khung junctional elements close lớn the cell periphery. These regions are flanked by clusters of surface membrane L-type Ca2+ channels và SR membrane RyR2-Ca2+ release channels. 2) Noncorbular SR in the cell interior also contains membrane regions that express RyR2 but bởi not show this proximity khổng lồ the cell surface. Depolarization of the cell surface membrane triggers entry of extracellular Ca2+ through the activation of ICaL, resulting in a local increase in i. This induces RyR2-mediated Ca2+-induced Ca2+ release at corbular SR. The resulting local elevation of i then initiates Ca2+-induced Ca2+ release và its propagation through adjacent, deeper regions of noncorbular SR. This results in an inward, centripetal, propagated Ca2+-induced Ca2+ release wave sầu by noncorbular cytoplasmic SR within the cell interior (128, 419, 521, 710, 1335, 1338).

3. Recovery from excitation

Contractile relaxation follows reduction in the elevated i baông chồng to baseline levels. This permits Ca2+-troponin dissociation. Cytosolic is reduced by Ca2+ transport activity by SR Ca2+-ATPase (SERCA2), sarcolemmal Na+/Ca2+ exchange through the Na+/Ca2+ exchanger (NCX), & slow systems represented by sarcolemmal Ca2+-ATPase (PMCA) và mitochondrial Ca2+ uniport. The relative sầu contributions of these different Ca2+ transport mechanisms khổng lồ the restoration of resting levels of i varies with species (110). In rabbit ventricular myocytes, SERCA2a activity eliminates 70%, NCX removes 28%, and the slow systems ∼1% of released Ca2+ with similar levels for ferret, dog, cat, guinea pig, and human ventricle (450). Corresponding contributions in rat and mouse ventricle are 92, 7, & 1%, respectively (78, 140, 653).

Of these processes, the NCX exerts potentially important effects on membrane potential through its electrogenic effects. These can contribute khổng lồ arrhythmic tendency. Each cycle of NCX activity translocates 1Ca2+ from the intracellular to the extracellular space in return for a transfer of 3Na+ in the opposite direction. This results in a net current (INCX) whose reversal potential depends on both the Na+ & Ca2+ Nernst potentials, ENa & ECa, giving ENCX = 3ENa − 2ECa. ENCX therefore falls within the range of voltages traversed by normal physiological activity. Consequently, whether INCX takes an inward, depolarizing or outward, hyperpolarizing direction varies with the changes in both i & membrane potential that take place through the cardiac cycle. Thus INCX takes an inward direction & exerts a depolarizing effect on membrane potential under conditions when i is elevated & thereby drives Ca2+ efflux. Conversely, INCX takes an outward direction exerting a hyperpolarizing effect on membrane potential when i is relatively low, thereby driving Ca2+ influx. The pattern of INCX activity also varies with species-related differences in AP.. wavesize. The long plateau phase in rabbit ventricular APs results in a sustained INCX-mediated Ca2+ influx through the APhường. plateau phase (165). Following repolarization, a large outward electrochemical gradient then drives Ca2+ efflux. In contrast, the short AP. in rat ventricles results in a rapid initial INCX-mediated Ca2+ influx, but this is followed by a more marked Ca2+ efflux. This results in a more rapid removal of the added Ca2+ load arising from electrical excitation and a lower subsequent diastolic NCX activity (1042). Either of these effects potentially modify the action potential duration (APD) (Figure 1,A & B) (265, 1025).

Of the overall energetic cost of contractile và excitable cardiac activity, ∼60–70% of this cellular ATP.. is consumed by cardiac muscle contraction. The remainder maintains Ca2+ homeostasis and the transmembrane ion gradients.

1. Electrical current flow between cardiac cells

The subsequent propagation of cellular-level events through conducting atrial or ventricular tissue first involves a local spread of electrotonic excitation currents. These are driven typically in the more rapidly conducting cardiac tissues by INa (137, 496, 1043). Cable theory classically describes this current flow along a constant intracellular, axial resistance ra from one depolarized myocyte to its quiescent neighbor (492, 577). In cardiac tissue, ra reflects the electrical resistances formed, respectively, by the cytosol và intercellular gap junctions connecting successive adjacent cells. An axial current, ia, having traversed the resistance ra, then discharges the membrane capacitance, centimet, of neighboring quiescent cells. Where this resulting depolarization exceeds the activation threshold of its voltage-sensitive Na+ channels, this results in a regenerative sầu production of further transmembrane depolarizing currents in that cell. This continues the AP propagation process. Thus, in cardiac cells, resistance lớn conduction through intercellular gap junction channels, the membrane capacitance, & the magnitude of INa are critical to APhường propagation (958).

2. Determinants of conduction velocity

The velocity θ of AP conduction along a simple one-dimensional unikhung cylindrical fiber of excitable tissue can be approximated by a nonlinear cable equation (550, 902). This has been applied to biological membrane with circuit elements that each incorporate a capacitance of unit fiber length, cm (typically expressed in units of μF/cm) in parallel with a linear membrane resistance of unit fiber length rm (kΩ·cm). The membrane additionally contains further, nonlinear, time- & voltage-dependent, membrane conductances representing the properties of its contained individual ion channels. These together generate the time (t)-dependent total membrane ionic current ii (A/cm) in unit fiber length, x (cm). Successive sầu circuit elements are connected by terms arising from cytoplasmic resistances & the gap junction resistances between cells (see sect. IV) (262, 1181). Any one of these factors could be modified by changes including tissue fibrosis or inflammatory processes (see sects. V, E & F, và IXA).

The membrane potential V at any given membrane site then depends on the charging of its unit length by currents traversing the membrane, ii, as well as the axial current flow, ia, coming from neighboring regions along the length x of the membrane area in question through the equation

This equation reduces at constant conduction velocity, θ = dx/dt to lớn

This simplified interpretation identifies ra, cm, & ii as key determinants of θ, although interdependences between some of the terms involved preclude analytic solution (471). Explicit prediction instead requires numerical solution of a stiff equation involving iterative sầu estimates of θ (492). This is particularly given potential further contributions from other membrane components including transverse tubular membrane resistances và capacitances, tubular luminal geometry and its resistance, & nonlinear capacitances (9, 457, 1047). A full cable analysis of AP. propagation would also be required to incorporate the three-dimensional nature of cardiac geometry.

Nevertheless, a number of useful, simple relationships between θ and its determinants arise from computational studies of one-dimensional electric current flow in skeletal muscle fibers whose APs upstrokes are similarly dominated by fast INa (330, 567, 880). These confirm the importance of iNa during the AP upstroke, and that the maximum Na+ current
iNa(max)α log(R2=0.9965)(3)

PNa(max) is the maximum permeability produced by the fast Na+ channels. It is accordingly dependent on Na+ channel density. Of the key determinants of θ, ra does not influence the APhường. waveform. It thus does not influence either its rate of upstroke voltage change, as given by the first derivative sầu (dV/dt), or its second derivative (d2V/dt2), though the cable Equation 2 predicts that θ2 α 1/ra. In contrast, increased centimet does alter APhường wavesize. It reduces both dV/dt and d2V/dt2 as well as reducing θ, giving the simple approximations
θ2 α 1/cm(4)
(dV/dt)max α log(cm)(5)
(d2V/dt2)max α1/cm(6)

The subscript max designates the maximum value of the parameter in question. Finally, it is difficult khổng lồ obtain analytic relationships between iNa(max) và θ. Nevertheless, it is possible khổng lồ demonstrate the straightforward empirical relationship
θα iNa(max)(7)

& the following effects of iNa(max) upon AP wavekhung
(dV/dt)max αiNa(max)3(8)
(d2V/dt2)max α iNa(max)3(9)

This cable analysis, confined to a simple cylindrical, geometrically one-dimensional, structure, can be generalized to a continuous electrically coupled myocyte network. This provides cable equations extended from one to three dimensions analyzing the conduction velođô thị resulting from a matching of current & load (577, 599). Such an approach has been used to characterize the passive sầu cable properties of cardiac muscle including its relationships between dV/dt và macroscopic (>1 mm) propagation and altered cell to lớn cell coupling (576, 1246).

3. Repolarization gradients & action potential wavelength

Finally, normal atrial & ventricular myocardium shows a highly ordered sequence of AP. repolarization and return of the membrane lớn resting conditions. In the ventricular myocardium, this typically proceeds transmurally from epicardium lớn endocardium & from apex lớn base. These features reflect regional differences in K+ channel mật độ trùng lặp từ khóa & kinetics. This results in the normal spatial repolarization gradients that may normally protect the orderly electrical and mechanical activation sequence. This thereby ensures correctly timed & coordinated mechanical activation & relaxation of the chamber concerned. In contrast to the ventricles, the thinner walled atria vày not show a marked transmural differentiation inkhổng lồ epicardial và endocardial tissues. The geometrical distribution of excitable events then occurs only within the plane of the atrial wall.

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Together, the velođô thị θ of APhường propagation and the recovery parameters of APD or the effective refractory period (ERP) define the AP wavelength (λ = θ·APD or θ·ERP). The APD reflects the period during which the membrane deviates from its normal resting value. It may closely correlate with the ERPhường in normally functioning canine và human hearts (243, 329, 624). The latter provides an indication of the time during which there is reduced likelihood of ectopic or reentrant action potential activation in the membrane behind the propagating excitation wavefront. However, ERPs can be selectively affected by factors that need not similarly affect APD. These include alterations in the maximum amplitude and activation or inactivation kinetics of INa and IK, the amplitudes và durations of applied stimuli and myocyte injury & ischemia (975). Subsequent sections will consider VERP-ERPhường differences & their significance in proarrhythmic situations including Brugadomain authority syndrome (sect. VC5) (50, 734) và hypokalemia (sect. VE)(978).

However, measurement of ERPhường, typically from the shortest S1S2 interval following the last (S1) pacing stimulus at which a subsequent extrasystolic S2 stimulus elicits an APhường, itself poses problems under particular experimental circumstances. Thus 1) some protocols are not amenable to such direct determinations of ERPs, yet 2) ERPs themselves vary with pacing protocol. 3) The observed ERPs critically depover on the relationship between stimulus & recording sites. A detectable AP.. requires its successful propagation through the entire tissue pathway from stimulating khổng lồ recording electrode. The resulting ERPhường. consequently actually reflects recovery from refractoriness over the entire line of tissue between stimulus & recording sites. 4) This condition poses further problems for determinations of spatial ERP.. heterogeneities between recording sites. The difficulties are compounded if stimulus & recording sites have sầu differing ERPs. 5) ERPhường determinations are further affected by conduction velocities in the paths intervening between stimulus và recording sites. This was demonstrated in comparisons of ERPhường measurements at the stimulus site itself, ERPs, và the ERPr, given by the time interval separating AP.. upstrokes, at the recording site. ERPr then did not equal ERPs when the conduction velocity of the AP.. produced by the S1 stimulus differed from the conduction velocity of the APhường. produced by the S2 stimulus. These discrepancies were accentuated at high pacing rates cđại bại to lớn refractoriness, và with increasing distance between stimulation and recording sites (734). 6) Whereas absolute refractory period may be regarded as an invariant value, ERP depends on the value of the effective stimulus intensity at the site of membrane excitation. Thus an adaptive S1S2 protocol demonstrated differing ERPs corresponding to differing magnitudes of S2 extrastimulus. Representations involving ERP, rather than APD, are thus strongly dependent on applied stimulus voltage (281).

The wavelength parameter nevertheless provides a useful description of the spatial extent of excitation by the traveling wave. Larger values of λ would result in a reduction of the likelihood that areas of depolarization & repolarization meet on encountering tissue heterogeneity. The resulting safety factor would then ensure that the traveling wave completely passes over the heterogeneity without disruption (1251). Conversely, a decreased value of λ would increase the likelihood of a wave sầu breakup inlớn inkhổng lồ multiple wavelets, formation of scroll-waves (244, 866, 1317), và a positive feedbachồng formation of further wavebreaks giving wavelets along chaotic conduction pathways corresponding to VF (1084). For example, where alterations in heart rates decrease APD, ERP.., or θ, they could thereby alter AP wavelength λ & thereby potentially exert arrhythmic effects (595, 753).

Figure 2 illustrates such situations for a sequence of murine APhường waveforms (753). The relevant parameters can be quantified, in terms of their basic cycle lengths (BCL), APDs at 90% repolarisation (APD90), latencies, and corresponding diastolic intervals (DIs) at 90% repolarization (DI90) separating the current và preceding action potentials. Together these yield active and resting wavelengths λ" và λ0" (Figure 2A). The latter sum together lớn give sầu a basic cycle distance, BCD" (Figure 2B). When an AP with long λ" passes over a heterogeneity that can potentially cause conduction bloông chồng, the bachồng of the propagating wave blocks retrograde propagation. This leaves only an orthograde excitation wave sầu (Figure 2C). In contrast, when λ" is short, the baông chồng of the wave passes the heterogeneity before retrograde excitation has passed through the unidirectional block. This initiates a new propagating retrograde wave which potentially sets up a sustained reentrant circuit (Figure 2D).

Figure 2.Extension of cable analysis to action potential wavelength, wave-break, and re-entry. A: typical murine monophasic right ventricular action potential (AP) waveform, indicating basic cycle length (BCL), action potential duration at 90% recovery (APD90), latency & diastolic interval (DI) of the current (nth) and preceding <(n−1)th>AP. B: these variables yield the active và resting wavelengths λ" and λ0" for which the basic cycle distance, BCD" = λ" + λ0". C: orthograde propagation of an APhường. with long λ" over a heterogeneity results in the baông chồng of the propagating wave blocking retrograde propagation. D: propagation of an AP.. with a short λ" results in the baông xã of the wave sầu passing the heterogeneity before retrograde excitation has crossed the unidirectional block. This results in initiation of a new propagating retrograde wave sầu và a re-entrant circuit.

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1. Triggering events at the cellular level

Arrhythmias result from an inappropriate generation, or a breakdown in the orderly sequencing, of cardiac electrical activity. They often follow triggering events, and then take place in tissue with intrinsic instabilities resulting in arrhythmic substrate (284, 529, 931, 1111). Events reflecting such phenomena could occur at the single-cell level, during propagation of excitation at the tissue cấp độ, or at the level of entire cardiac chambers (560, 981).

At the cellular level, triggered activity results from extrasystolic membrane depolarization that could potentially generate premature APs, & therefore, triggered beats, following an otherwise normal AP., if the voltage changes that they produce are sufficiently large. Of these, early afterdepolarizations (EADs) intercept the repolarization time course of a prolonged AP. They thereby permit time for L-type Ca2+ channel recovery from inactivation in a still depolarized membrane. The reactivated inward ICaL then produces a further depolarization. This initiates a positive feedbachồng process resulting in the afterdepolarization potentially triggering APhường firing (498). In contrast, delayed afterdepolarizations (DADs) follow full APhường repolarization. They can result from an enhanced SR Ca2+ release. This in turn increases activation of electrogenic NCX or Ca2+ activated Cl− transient inward (Iti) currents. DADs are associated with conditions of Ca2+ overload as occurs in digitalis toxicity và catecholaminergic polymorphic ventricular tachycardia (CPVT) (509). In the atria, triggering can also arise from the pulmonary or the superior caval veins và may thereby trigger episodes of AF (190) (see sects. VIA and VIIA).

Rarer causes of arrhythmias initiated by abnormal APhường triggering at the cellular cấp độ include the enhanced automatiđô thị resulting from accelerations in depolarization of pacemaker tissue. This might follow increased sympathetic activity, hypokalemia, or pharmacological intervention. In addition, parasystole could result from a parallel activation of two or more pacemaker regions (32).

2. Spatial electrophysiological heterogeneities at the tissue level

At the tissue level, failure of the APhường. wave sầu lớn completely extinguish after normal activation, leading to reexcitation of regions that had hitherto lớn recovered excitability can result in a reentrant excitation. This can occur in the presence of spatial electrophysiological heterogeneities that result in 1) an obstacle around which the APhường can circulate provided 2) this occurs with slowed conduction velocities that would permit each region khổng lồ recover excitability before the wave sầu returns, in the presence of 3) a unidirectional conduction block. The latter might occur with spatial gradients in the latency separating stimulation và depolarization or the time between depolarization & the kết thúc of the ERPhường (see sect. VC) (740). Either would prevent the wave sầu from self-extinguishing (778).

Figure 3 reconstructs the generation of arrhythmic substrate through such a combination of conditions. It illustrates the consequences of introduction of a slow conducting myocardial pathway passing through nonconducting myocardium (path 1; dark gray). This is bordered by a second pathway of normal myocardium (path 2; white). A normal AP (xanh arrow) would propagate along path 2 following excitation (Figure 3Ai). The myocardium then becomes refractory. As indicated above sầu (see sect. IC2), the resulting normal action potential traveling along path 2 possesses an excitation wavelength λ (yellow region). Consequently, the impulse conducting along path 1 cannot reenter the circuit as it would collide with refractory tissue in path 2 (Figure 3Aii). Similarly, when an abnormal impulse from an ectopic focus is triggered immediately following the normal AP, it cannot enter path 1 as this remains refractory (Figure 3Bi). It therefore splits at the end of path 2 to conduct retrogradely along path 1 và orthogradely along path 2 (Figure 3Bii). In contrast, a self-perpetuating reentrant excitation can result when 1) an action potential conducting retrogradely along path 1 enters the beginning of path 2 (Figure 3Ci) under conditions of 2) reduced conduction velocity (θ) and/or reduced effective sầu refractory period (ERP). The latter result together in a reduction in excitation wavelength (λ = θ × ERP), to values smaller than the dimensions of the available circuits (Figure 3Cii). This results in persistent reentrant excitation (567).

Figure 3.Conditions underlying generation of re-entrant arrhythmia. A: basic features of arrhythmic substrate, consisting of slow conducting myocardial pathway (path 1; dark gray), nonconducting myocardium, và second normally conducting pathway (path 2; white) (i). Normal action potential (blue arrow) propagates with velocity θ và effective refractory period (ERP) resulting in propagation wavelength (λ = θ × ERP) (yellow region) along path 2. It initiates a slow conducting impulse traveling along path 1 (i). In normal activity, the latter impulse cannot re-enter the circuit as it collides with refractory tissue in path 2 (ii). B: an abnormal triggered impulse immediately following the normal action potential cannot enter path 1 as this remains refractory. C: self-perpetuating re-entrant excitation occurs when a retrogradely conducting APhường along path 1 (i) enters the beginning of path 2 with reduced conduction velocity và effective refractory period & therefore reduced excitation wavelength smaller than the dimensions of the propagation pathways.

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Data from both canine right ventricular (RV) wedge preparations (801, 802) và the Scn5a+/ΔKPQ mouse Mã Sản Phẩm (see sect. VIB) further implicate reentry arising from repolarization abnormalities as exemplified by their epicardial dispersions of repolarization in triggering ventricular arrhythmia. The simplest example of this might arise from substrate for reentrant excitation arising from relative sầu changes in two key parameters describing the recovery from excitation. Thus windows of reexcitation have been suggested in situations where critical intervals result from positive time differences between full action potential repolarization và the refractory period. These parameters are often quantified by APD90 và VERP, respectively. This could take place within, or between, adjoining areas of myocardium, and is exemplified in section VE4 (978).

At the cấp độ of individual cardiac chambers, disruption of the normal sequence of repolarization following the depolarization wave accentuates arrhythmic tendency (1012). Mammalian ventricular myocardium normally shows a consistent và regular sequence of repolarization. This proceeds from epicardium lớn endocardium resulting in a transmura l repolarization gradient that optimizes the normal sequence và coordination of electromechanical activation và relaxation (see sect. VIA4). These spatial differences are mainly determined by regional differences in repolarizing K+ channel densities. Disturbances in these gradients may permit regions of depolarization to lớn reentrantly reexcite already recovered areas (see sect. VIA2).

Transmural gradients may be particularly important in producing repolarization differences across relatively short distances. They have sầu been implicated in a number of both canine models subject to lớn pharmacological manipulation và murine models genetically modified to reproduce Brugadomain authority syndrome (BrS) (see sect. V) & long QT syndrome (LQTS) (see sect. VI). In addition, a number of animal models show ventricular, base-to-apex, heterogeneities in AP characteristics (see sect. VI). In human clinical situations, increases in this dispersion have sầu been associated with arrhythmogenesis in cardiomyopathies & have been related to lớn increased incidences of T wave sầu alternans and VT (181). Finally, left-right interventricular differences in APD have been implicated in arrhythmogenesis in BrS. BrS patients show characteristic right precordial electrocardiographic ST elevation, right bundle branch bloông xã, và changes specific to lớn RV epicardial AP waveforms (605) (see sect. VD).

3. Temporal electrophysiological heterogeneities at the tissue level

Temporal electrophysiological heterogeneities may appear as beat-to-beat variations in APhường amplitude or duration. These instabilities have been clinically associated with the appearance of alternans in electrical properties between beats. T-wave alternans reflecting alternating time courses in successive ventricular APs classically precedes breakdown of regular electrophysiological activity and an onphối of major arrhythmias. Both T-wave sầu alternans & dispersion of the QT interval thus constitute risk stratification markers in both patients susceptible to lớn sustained ventricular arrhythmias (46, 823, 966) & experimental situations (872). At the cellular level, several hypotheses have suggested possible, potentially coexistent, mechanisms. Voltage-driven alternans can arise from instabilities in membrane voltage resulting from steep APD restitution properties (413, 838). These can reflect the properties of depolarizing, INa, or repolarizing currents including Ilớn (701), Kir3.x in the case of atrial alternans (126), and currents giving rise to EADs (1005). Membrane voltage is also influenced by the Ca2+-sensitive ICaL, INCX, IKs, và Ca2+-activated SK channels (1004, 1050, 1309, 1333). Nonlinearities can occur in intracellular Ca2+ cycling itself (894, 9trăng tròn, 1218). The latter can become unstable with SR Ca2+ overload, RyR2 sensitization, or at high pacing rates. These can result in steep SR Ca2+ release versus SR Ca load relationships giving Ca2+ restitution properties predisposing to i-driven alternans (204, 1050). At the tissue màn chơi, the resulting alternans may be spatially concordant in which the alternations in adjacent regions of a tissue are in phase, or discordant, when these are out of phase.

APD alternans may be an important mechanism for the generation of arrhythmic substrate. Spatially concordant alternans is not itself arrhythmogenic. However, it may represent a stage that precedes the development of discordant alternans. Discordant alternans in adjacent tissue areas produces APD gradients across their intervening regions which are separated by a nodal line region not showing alternans (872, 1236). Discordant alternans greatly amplifies the dispersion of refractoriness, generates regions of conduction block, and predisposes to figure-of-8 reentry phenomena. Triggered activity within the area with the short APD that propagates directly to lớn the nodal line then likely collides with the electrical activity in the area with the long APD while this is still depolarized và refractory. It will then become extinguished. However, where its propagation is less direct over a longer distance, it would reach the nodal line at a later time when the area with the long APD has recovered (Figure 3 in Ref. 1250). It would then induce reexcitation và a reentrant circuit leading lớn VT, wavebreak, & evolution into VF (928, 1236).

4. Heterogeneities arising from restitution phenomena

APD restitution phenomena were first reported in classic cardiac electrophysiological papers describing alternations in excitation duration, later measurable by intracellular recording as APDs, with increasing heart rate (436, 778). The subsequent classical analysis described below arose from observations that APDs recorded from canine papillary muscle decreased with increasing steady-state pacing rate. The latter findings had led to the development of a restitution theory seeking khổng lồ integrate such observations (838). This theory has been recently successfully applied lớn murine hearts (979, 982) (see sects. VC6 and VIA5).

The restitution analysis seeks to graphically predict the occurrence and magnitude of alternans with alterations in heart rate (Figure 4A). It does so through the expected oscillatory properties of a negative feedbaông xã system. The output of such a system (O) is considered lớn be the result of an amplification G of an input I. The latter is itself controlled by an independent variable, X

Figure 4.Temporal heterogeneity in the generation of re-entrant substrate. A: classical restitution curves in which action potential duration (APDn) of the nth APhường decreases with the decreasing, preceding, (n−1)th, diastolic interval (DI) observed at successively shortened basic cycle lengths (BCL). The accompanying progressively increasing slope requires successively greater number of cycles of alternans lớn intervene before the system reaches a new steady-state APD (points 1 & 2). When unity slope is reached, alternans become sustained (point 3). Slopes exceeding unity result in waxing oscillations (point 4) in APD. This culminates in conduction block and/or tachyarrhythmia resulting from wave-break. B: fuller analysis of generic restitution function relating APD90 corresponding lớn the APD at 90% APhường. recovery to the corresponding DI90. In addition khổng lồ conventional measures of critical diastolic interval (DIcrit) and maximum gradient (mmax), this maps the maximum APD (APDmax) at low heart rates, DI90 at the effective refractory period (DIERP), and the horizontal axis intercept of the restitution function (DIlimit), corresponding to lớn absolute refractoriness. This permits definition of conditions for stability (unshaded), instability (gray), as well as relative sầu (dark shading) và complete loss of capture (left shaded area). C & D: typical records reflecting arrhythmic phenotypes in monophasic action potential recordings from regularly paced (triangular markers) murine Scn5a+/− right ventricular (RV) epicardia showing nonsustained VT (BCL 134 ms) (C) và the initiation of sustained polymorphic VT (BCL 124 ms) (D).

The output O in turn influences the input, khổng lồ an extent which depends on a fraction of the output (F) và the independent variable (X)

The solution of these simultaneous Equations 10 & 11 corresponds to the points of their graphical intersection. These thereby yield the phối points giving the input đầu vào I and output O at any value of X. The original analysis adopted as input đầu vào variable the diastolic interval (DI) over which the membrane is restored lớn the resting potential. Over this period, the membrane is recovering following the AP.. The output variable is the APD. This is itself dependent on the preceding DI. Thus, for any given, nth, beat

The independent variable controlling DI is the BCL. The DI in the subsequent, (n+1)th beat, DIn+1, depends on both the BCL and the APD in the previous, nth beat, APDn

An A curve was obtained by plotting the output variable of APD against the đầu vào variable of DI. A family of D lines each taking the size

with a consistent negative unity gradient but variable ordinate intercepts set by the BCL was then plotted between the same axes. The intersection between the D line và the A curve would give sầu the solution for the steady-state APD và DI.

A perturbation in heart rate would result in an immediate transition between two separate D-lines representing the respective sầu BCLs. A horizontal line from the steady-state point on the A curve to lớn the new D line would then give sầu the magnitude of the first subsequent DI. A vertical line drawn from there lớn the corresponding A curve sầu would give sầu the corresponding subsequent APD. Graphical representations for the different cases are shown numbered 1–4 in Figure 4A. Each case would yield different predictions for the outcomes generated by continuation of this process. These would depkết thúc on the gradient of the A curve at its intersection with the D line, and its variation with DI in this region.

Where this intersection occurs in a region of the A curve sầu where its slope is zero (Figure 4A, point 1), a final steady-state APD is immediately reached without oscillations. Where the slope at the intersection falls between zero và unity (Figure 4A, point 2), the successive projection lines converge towards and ultimately attain the mix point. Each corner on the A curve then represents an individual oscillation, producing a transient alternans. With an intersection at a critical DI, DIcrit, where the the A curve assumes a unity slope, the projection lines khung a square. The oscillation then does not converge (Figure 4A, point 3). This results in a sustained alternans whose magnitude is determined by the form size of the square. Finally, where the intersection takes place in a region on the A curve where its slope is greater than unity, the progressive sầu projections take a centrifugal trajectory. They thus veer away from the left-hvà limit of the A curve, producing conduction bloông chồng (Figure 4A, point 4). This state, particularly when heterogeneous across the myocardium, may cause reentry (754).

These different conditions can then be related lớn the remaining parameters describing cellular excitability in a fuller generic analysis of the restitution function. Figure 4B illustrates this development using the relationship relating APD90 lớn DI90 through different BCLs. In addition to the conventional measures of critical diastolic interval (DIcrit) & maximum gradient (mmax) this maps the maximum APD, APDmax, at low heart rates, DI90 at the effective sầu refractory period (DIERP), và the horizontal axis intercept of the restitution function (DIlimit) corresponding khổng lồ absolute refractoriness. These additional limits permit definition of different stability conditions within the plane of the restitution function. Thus stability would correspond to lớn the condition when the gradient of the restitution function, m ≤ 1 as outlined above (unshaded areas). Instability would be expected under conditions when DIcrit > DI90 > DIERP (filled areas). This would manifest in occurrence of either nonsustained (Figure 4C) or sustained arrhythmia (Figure 4D). These are exemplified in the recordings from murine Scn5a+/− RV epicardia at two respective sầu BCL values (134 & 124 ms, respectively). Relative loss of capture would be expected in the interval DIERP > DI90 > DIlyên ổn, (dotted areas) và complete loss of capture when pacing takes place at a BCL shorter than the absolute refractory period when DI90 lim (hatched areas) (752).

The first restitution (A-) curves were deduced from transmembrane APs in isolated frog (Rana catesbiana) ventricles. These were paced at successively higher rates until refractoriness was reached. These gave sầu a wide range of DIs. APD then varied minimally at low pacing rates. However, with increases in rate, the A-curve gradients became progressively but reproducibly steeper. Recordings obtained immediately following rate changes were variable. They showed a hysteresis above và below the steady-state line for accelerating & decelerating rates, respectively.

Parameters other than APD, such as voltage, may also show alternans và could be similarly graphically analyzed. However, although often occurring together, the existence or extent of voltage amplitude alternans did not parallel the magnitude of duration alternans. Furthermore, wide interspecies variations exist in the time course and the final steady states of adaptations to change in BCL. Imposed increases in heart rate most frequently result in initial reductions in APD with reduced DI, then increasing khổng lồ nevertheless still reduced steady-state APD values, in human, guinea pig, mouse, và frog ventricular APs. However, APD initially lengthens then rapidly decreases khổng lồ shorter values expected at shorter DI in rabbit, dog, và cat ventricles. This likely reflects incomplete Ikhổng lồ decay in rabbit and transient L-type Ca2+ current facilitation in dog và mèo. Finally, APD actually lengthens và remains prolonged with decreased DI in rat heart. Ca2+ homeostasis has been implicated in restitution changes invoking actions of i upon the activity of numerous other channels and carriers within the cell (166). Ionic mechanisms for APD accommodation lớn rate changes remain unclear. They almost certainly involve sầu inactivation processes in depolarizing INa and ICa currents or enhancement of repolarizing K+ currents, with both processes accumulating with successive sầu APs. However, there are numerous differing reports on their relative sầu importance. This has hampered attempts at in siliteo modeling of APD restitution. Recent clinical reports similarly suggest complexities in the use of such plots in predicting human arrhythmia (818).

Conduction velothành phố restitution plots of θ against DI similarly reflect the changes in θ with DI in consecutive sầu APhường waves. Conduction velođô thị alternans results in a compression and rarefaction of APs as they travel through the tissue. Slowed θ also reduces the distance between nodes. This results in a higher number of nodes thus predisposing khổng lồ reentry. θ restitution thus depends primarily on Na+ channel và intercellular coupling properties, whereas APD restitution is also affected by Ca2+ (212, 530), and K+ channel properties và is thus engaged at lower pacing rates (928). In silico modeling studies suggested that θ alternans initiated at higher pacing rates may be responsible for the breakdown of concordant to discordant alternans (1236). However, θ restitution, as represented by plots of θ against DI, are not amenable to the systems analysis of the kind illustrated in Figure 4 & Equations 10–14. Thus the variable θ does not directly feed into that of DI. Furthermore, θ restitution is primarily concerned with the wavefront, whereas APD restitution describes the recovery from excitation that follows (753). Nevertheless, a recent analysis has unified restitution analysis involving APD & θ, respectively, into lớn a single λ restitution analysis. This may offer a more general approach relating restitution conditions khổng lồ arrhythmic tendency (see sect. VC6) (753).

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