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  • br Alternans and arrhythmogenesis in different clinical cond

    2019-06-17


    Alternans and arrhythmogenesis in different clinical conditions APD alternans, whether spatially concordant or discordant, can produce arrhythmias. For example, spatially concordant alternans themselves can produce 2:1 conduction block, thereby initiating re-entry [48]. Nevertheless, discordant alternans are considered to be more arrhythmogenic. They can produce large spatial gradients in repolarisation and refractoriness, which can result in local conduction block of a premature extrasystole (such as a premature ventricular complex, PVC [37]), thereby facilitating re-entry [23,49]. They can also promote phase 2 re-entry involving either a fixed or a variable Ito, allowing antegrade and retrograde phase 2 re-entry, respectively [50]. These mechanisms for producing spatially discordant alternans are important in a number of clinical conditions, potentially causing lethal arrhythmias. In heart failure, there is extensive ion current remodeling with a lower threshold for inducing APD alternans [51]. APDs are prolonged due to downregulation of potassium currents and increased late sodium current [30]. This would allow the steep portion of APD restitution to be engaged, and therefore generation of spatially concordant alternans. These can become discordant in the presence of conduction abnormalities [30], cardiac fibrosis [52], or abnormal Ca2+ handling dynamics, such as increased SR Ca2+ leak [53], decreased SERCA pump activity [54], increased NCX currents [55], or steeper fractional release of SR Ca2+ content [56]. In catecholaminergic polymorphic ventricular tachycardia (CPVT), mutations in the ryanodine receptor lead to diastolic calcium leak and generation of discordant Ca2+ alternans [57,58]. Long QT syndromes are characterized by APD prolongation, a reduction in repolarization reserve, and increased APD restitution gradients leading to the production of APD alternans. Spatial heterogeneities in repolarization are exacerbated due to differences in ion channel MRS 2768 tetrasodium salt and heterogeneities in restitution across the myocardial wall. Other pro-arrhythmic conditions are clearly associated with a flatter APD restitution curve, but discordant alternans can be generated when regional differences in restitution lead to spatial heterogeneities in APDs [59]. In myocardial ischemia and sodium channel blockade, CV restitution may be more important in the conversion of concordant alternans to discordant alternans [60]. Increased beta adrenergic drive, which can occur in heart failure or exercise, can increase the maximum gradients of APD restitution and produce discordant alternans [61]. Regardless of the mechanisms generating these arrhythmogenic alternans, the final common pathway involves wavebreak, conduction block, and the initiation and maintenance of re-entrant arrhythmias [62]. It should be recognized that alternans are only one factor in determining arrhythmogenesis. An anti-arrhythmic state can occur even in the presence of both steep APD restitution and discordant alternans, as exemplified by hypokalemia [19]. Heptanol, a gap junction uncoupler, was shown to exert anti-arrhythmic effects in hypokalemia by influencing VERP alone [63]. This finding is perhaps surprising, given that reduced electrotonic coupling should exacerbate dispersion in APDs and promote arrhythmogenesis.
    Future therapies The question of how understanding the cardiac dynamics can enable us to devise better pharmacotherapy for arrhythmia management persists. Numerous studies using animal models have demonstrated that the anti-arrhythmic actions of many drugs are in part mediated by their effects on cardiac dynamics. These include traditional agents such as beta-blockers as well as novel drugs such as late sodium current blockers and gap junction openers [64–66] (Fig. 7). Gap junction inhibitors can exert anti-arrhythmic effects by prolonging effective refractory periods [63,67]. Moreover, mild loss of gap junction function in non-uniform tissue may paradoxically increase CV and improve the safety margin of conduction [68]. This in turn could remove unidirectional conduction blocks, converting them into bilateral conduction [69]. In contrast, gap junction enhancers can improve conduction and reduce the spatial heterogeneities in repolarization and refractoriness, thereby suppressing discordant alternans and arrhythmogenesis. Their effects on calcium dynamics are complex, depending on the nature of Ca2+→APD coupling. The differences in Ca2+ transient between adjacent cells are amplified in the case of negative coupling, but reduced with positive coupling [40]. Activation of stretch-activated channels exerts opposing effects on alternans, suppressing those that are concordant whilst exacerbating those that are discordant [22]. SAC inhibitors could potentially exert anti-arrhythmic effects by suppressing discordant alternans. Discordant alternans can also be inhibited by late sodium channel blockers [65], ryanodine receptor stabilizers [57] or anti-fibrotic agents [70], which would prevent conduction block and inhibit arrhythmogenesis. Some of the examples described above illustrate the difficulty in predicting the overall electrophysiological effects of a drug, and some may exert their anti-arrhythmic effects without influencing restitution [71,72]. Future efforts therefore require a computational strategy in which modeling of the heart can be achieved at different levels of biological organization to take into account of the complex spatiotemporal properties of cardiac dynamics.