Dispersion Of Recovery Research Articles

Dispersion of Recovery and Vulnerability to Re-entry in a Model of Human Atrial Tissue With Simulated Diffuse and Focal Patterns of Fibrosis.

Fibrosis in atrial tissue can act as a substrate for persistent atrial fibrillation, and can be focal or diffuse. Regions of fibrosis are associated with slowed or blocked conduction, and several approaches have been used to model these effects. In this study a computational model of 2D atrial tissue was used to investigate how the spatial scale of regions of simulated fibrosis influenced the dispersion of action potential duration (APD) and vulnerability to re-entry in simulated normal human atrial tissue, and human tissue that has undergone remodeling as a result of persistent atrial fibrillation. Electrical activity was simulated in a 10 × 10 cm square 2D domain, with a spatially varying diffusion coefficient as described below. Cellular electrophysiology was represented by the Courtemanche model for human atrial cells, with the model parameters set for normal and remodeled cells. The effect of fibrosis was modeled with a smoothly varying diffusion coefficient, obtained from sampling a Gaussian random field (GRF) with length scales of between 1.25 and 10.0 mm. Twenty samples were drawn from each field, and used to allocate a value of diffusion coefficient between 0.05 and 0.2 mm2/ms. Dispersion of APD was assessed in each sample by pacing at a cycle length of 1,000 ms, followed by a premature beat with a coupling interval of 400 ms. Vulnerability to re-entry was assessed with an aggressive pacing protocol with pacing cycle lengths decreasing from 450 to 250 ms in 25 ms intervals for normal tissue and 300–150 ms for remodeled tissue. Simulated fibrosis at smaller spatial scales tended to lengthen APD, increase APD dispersion, and increase vulnerability to sustained re-entry relative to fibrosis at larger spatial scales. This study shows that when fibrosis is represented by smoothly varying tissue diffusion, the spatial scale of fibrosis has important effects on both dispersion of recovery and vulnerability to re-entry.

Genetic aspects in acquired long QT syndrome ? a piece in the puzzle

Torsade de pointes (TdP) is a serious complication which is induced by a large variety of cardiovascular and non-cardiovascular drugs. Many clinical conditions and risk factors for the occurrence of TdP during administration of drugs with a proarrhythmic potential have been identified. All such drugs have in common that they reversibly alter myocardial repolarization due to the prolongation of the action potential (acquired QT interval prolongation) which is per se not arrhythmogenic. TdP is initiated (acquired long QT (LQT) syndrome) only when a threshold level is reached leading to early after-depolarizations (EADs) and triggered beats together with a marked dispersion in recovery of excitability. The underlying mechanisms of TdP are not yet satisfactorily elucidated but, in general, alterations in cardiac ion currents which tune the normal action potential play a major role in arrhythmogenesis. Following recent advances in molecular biology and genetics, it has become clear that in some clinical instances (e.g. congestive heart failure or cardiac hypertrophy) ion channel genes become less expressed (down-regulated) and the consequent reduced ion currents (e.g. IKr) are likely to cause prolonged myocardial repolarization. In this setting, the use of drugs with action potential-prolonging properties could possibly be harmful and could not be compensated by the normal cardiac ‘repolarization reserve’. In congenital LQT syndrome some of the same ion channel components were found to be genetically altered, suggesting that either quantitative or qualitative changes of ion currents may be involved in ventricular arrhythmogenesis through similar mechanisms (‘final common pathway’). A variable clinical expressivity and, especially, an incomplete penetrance has been found in patients carrying the same LQT genotype, even when near-relatives, which raises the question on the frequency and importance of ‘silent’ (i.e. minor functional) ion channel gene mutations that may become functionally significant in presence of action potential prolonging drugs and other coexisting factors. The observation of adverse drug reactions in apparently healthy (‘normal heart’) individuals is suggestive of a genetic susceptibility for ‘acquired’ arrhythmias. This report reviews and summarizes the recent knowledge on unapparent ion channel gene mutations and preliminary concepts about ‘acquired’ arrhythmias.

Dispersion of ventricular repolarization and refractory period.

Time for primary review 34 days. In their classic studies published in 1964, Han, Moe and co-workers [1,2] established an association between nonuniform recovery of excitability and lowered fibrillation threshold. They concluded that “those agencies known to favour the development of ventricular fibrillation were found to increase the temporal dispersion of recovery of excitability, whether the average refractory period was reduced … or increased…. The results emphasise the importance of nonuniformity of excitability and conduction velocity during the relative refractory period in the induction of turbulent impulse propagation.” The purpose of this review is to describe the basis of dispersion in recovery of excitability in the ventricle and its association with arrhythmogenesis. Ventricular tachyarrhythmias are readily generated not only in acute ischaemia/infarction but also in hearts that have undergone remodelling following myocardial infarction [3–5]. Life-threatening arrhythmias are commonly seen in patients with previous myocardial infarction in the absence of new ischaemic events, as evidenced by the ability to initiate sustained ventricular tachycardia by programmed stimulation [6]. The risk of ventricular arrhythmias and sudden death in heart failure is inversely proportional to the left ventricular ejection fraction [7]. However, the Veterans Heart Failure Trial and other studies suggest that the proportion of deaths that are sudden is higher in patients with less severe LV dysfunction [8]. Such individuals are less likely to die from pump failure, hence they are at greater relative (but not absolute) risk of sudden death in comparison with patients with advanced heart failure. The classical prerequisites for the development of reentry are the presence of a potential circuit around an anatomical obstacle, unidirectional block, and sufficiently slow conduction to enable recovery of excitability in time for reexcitation by the depolarizing wavefront [9]. A feature of this type of reentry is the presence … * Corresponding author. Tel.: +44-141-211-4722; fax: +44-141-552-4683 stuart.cobbe{at}clinmed.gla.ac.uk

Variability of Recovery of Excitability in the Normal Canine and the Ischaemic Porcine Heart

Normal hearts: Refractory periods were determined at 12 to 15 intramural sites of the normal canine left ventricle during steady state regularly driven rates, after each of a series of four early premature beats, and after a long pause following a series of three premature beats. The dispersion in recovery of excitability, defined as the standard deviation of the mean refractory periods, was in absolute terms the same for all three situations. However, since mean refractory periods shortened after premature beats, in relative terms, dispersion of recovery of excitability was greatest after a series of four premature beats. The refractory periods of the specialized conducting system determined during the initial beats of a new, faster rate, showed that in subsequent beats, the refractory periods of the bundle branches are alternatively shorter and longer than the refractory period of the ventricular myocardium. An example of 'concealed bundle branch re-entry' is shown. It is concluded that normal hearts are well protected from sustained arrhythmias induced by changes in rate and rhythm. Ischaemic hearts: In isolated, Langendorff perfused porcine hearts, regional ischaemia was produced by clamping the left anterior descending coronary artery. The transmembrane potentials then were recorded within a distance of less than 1 mm from a stimulating electrode in the ischaemic zone. Refractory periods in the central ischaemic zone lengthened, those in the border zone shortened. Recovery of excitability in an ischaemic myocardium cannot be expressed in terms of intervals between stimuli alone: the quality of the premature response must also be taken into account. Typically, responses elicited well after completion of repolarization have markedly reduced amplitudes and upstroke velocities. Thresholds for stimulation increase in an ischaemic myocardium, and the use of strong test stimuli leads to artefactual results: evidence is presented that strong premature stimuli excite less injured cells far away from the stimulus site. Premature stimuli often induced arrhythmias. Presence of local responses in central ischaemic cells suggest regions of unidirectional block, creating circumstances where re-entry may occur. After a long pause, alternation in action potential amplitude and duration became more pronounced: possibly, a premature impulse elicited after a long pause encounters more regions of unidirectional block so that re-entry is facilitated.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of current pulses delivered during the ventricular vulnerable period upon the ventricular fibrillation threshold

The effect of current delivered to the myocardium as either a pulse or train of pulses upon the recovery of excitability and upon the subsequent threshold for initiating ventricular fibrillation was studied in open chest dogs. Bipolar epicardial electrodes delivered current during the vulnerable period, and a circular array of six electrodes surrounding the central current electrode recorded the time course of recovery of myocardial excitability. Increasing the current intensity of either a pulse or train of pulses at the central site increased the temporal dispersion in recovery of excitability among the six peripheral electrode sites. This increase in temporal dispersion was associated with a decrease in ventricular fibrillation threshold immediately after the application of current. The degree of temporal dispersion in recovery after the train was increased by coronary occlusion but decreased by administration of lidocaine. Increasing the intensity of current delivered during the vulnerable period increases the degree of inhomogeneity in recovery of the myocardium until a level is attained that allows multiple asynchronous reentry and fibrillation. Interventions that increase or decrease the intrinsic amounts of inhomogeneity in the myocardium modify the amount of “extra inhomogeneity” that the current pulses must add during a fibrillation threshold determination to bring the myocardium to a level for fibrillation. In this way current delivered during the vulnerable period assesses vulnerability to fibrillation. These experiments also suggest that the ventricular fibrillation threshold following premature ventricular beats evoked by malfunctioning cardiac pacemakers may be lower than that following spontaneously occurring premature beats at the same coupling interval.