Paced ventricular electrogram fractionation predicts sudden cardiac death in hypertrophic cardiomyopathy.

AIMS: Paced electrogram fractionation analysis (PEFA) has been assessed for the prediction of sudden cardiac death (SCD) in a large-scale, prospective study of patients with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: We determined the positive predictive value (PPV) of PEFA in relation to other risk factors for SCD and outcomes in 179 patients with HCM and no prior history of cardiac arrest. Patients were followed over a mean 4.3 years (range: 1.1-6.3 years). Thirteen patients had SCD-equivalent events: four of these patients died suddenly, three were resuscitated from ventricular fibrillation (VF), and six had implantable cardioverter-defibrillator (ICD) discharges in response to VF. PEFA identified nine of these patients and another 14 non-VF patients yielding a censored PPV of between 0.19 and 0.59 that was greater than the PPV that was the formal stopping point of the trial (0.18). Eighty per cent of patients were followed for 4 years or more. The PPV for the identification of SCD in this group was 0.38 (0.17-0.59). The use of two or more conventional markers to predict SCD identified five patients with SCD-equivalent events in the 4-year follow-up group and 42 other patients without events yielding a PPV of 0.106 (confidence limits 0.02-0.15). CONCLUSION: PEFA identifies HCM patients at risk of SCD with greater accuracy than non-invasive techniques and may have an important role in determining indications for ICD prescription.

Paroxysmal atrial fibrillation is associated with increased intra-atrial conduction delay.

AIMS: A novel electrophysiological technique, paced electrogram fractionation analysis (PEFA), which measures activation delay of stimulated beats through the myocardium, has shown that long delays in activation are strongly associated with sudden cardiac death due to ventricular fibrillation. The aim of our study was to determine whether there are differences in intra-atrial conduction in patients with and without paroxysmal atrial fibrillation (PAF) using PEFA. Twenty patients (15 women) in the mean age 54.7 +/- 16.6 years, scheduled for transcatheter ablation of their arrhythmias, were divided into two groups: 10 controls without PAF and 10 patients with PAF. METHODS AND RESULTS: During PEFA, pacing and recording catheters were placed in the coronary sinus (three sites: distal, mid, and proximal) and at four right atrium sites: crista terminalis (one site), RA isthmus (one site), and interatrial septum (two sites). The PEFA protocol involves pacing from one site and recording electrograms from other six sites. A decremental sequence, delivered at one site, had a cycle length of 490 ms (S1S1) with an extrastimulus inserted every third beat whose coupling interval (S1S2) is reduced by 1 ms on each occasion. This process is repeated from each atrial site. The S1S2 at which electrogram duration starts to prolong, and the increase in electrogram duration is determined at all sites. In three patients from the PAF group, atrial fibrillation was induced during PEFA and it was terminated by electrical cardioversion. No other complications were noted. The patients with PAF, compared with the control group, have abrupt increases in the electrogram duration, which occur, at significantly longer S1S2 (P < 0.0001). There were also significantly longer intra-atrial delays in the intrinsic deflection of the electrogram in PAF patient vs. control group (P < 0.0001). CONCLUSIONS: Comparison of PAF and non-AF patient groups showed that intra-atrial conduction delay start in the PAF group earlier (with longer S1S2 intervals) and they are significantly longer in the PAF group. This suggests that atria in patients with PAF are diffusely diseased and that the measured activation delays form one component of an arrhythmogenic substrate.

Delayed paced ventricular activation in the long QT syndrome is associated with ventricular fibrillation.

BACKGROUND: LQTS may cause sudden cardiac death (SCD), but the mechanisms linking gene mutations to ventricular fibrillation (VF) are unclear. OBJECTIVE: To determine whether ventricular activation delays in congenital long QT syndrome (LQTS) are associated with VF and to describe these delays clinically by measuring activation through ventricular myocardium after a premature extrastimulus. METHODS: Forty-six patients with LQTS, including 16 with VF (LQTS VF) were investigated, and the results were compared with those from 24 patients with hypertrophic cardiomyopathy and VF (HCM VF). Electrograms in response to premature stimuli were analyzed for increases in electrogram duration (DeltaED) and the S1S2 coupling intervals at which electrogram latency starts to increase (S1S2(delay)). Two piecewise continuous straight line segments were fitted to the last electrogram deflection as a function of S1S2 interval in the LQTS and HCM VF populations, and the difference in their gradient (alpha) was taken as an index of the abruptness of the onset of this delay. RESULTS: Thirteen LQTS VF and six LQTS non-VF patients had values of DeltaED and S1S2(delay) comparable to those in HCM VF patients, while the remainder (three LQTS VF and 24 LQTS non-VF) had lower values (P<.001). There was only a weak correlation between delay and the corrected QT interval. The HCM and LQTS VF patients could be separated by the value of alpha (P<.01), with the LQTS patients having a more abrupt onset of delay. CONCLUSIONS: Large delays in ventricular activation after an extrastimulus occur in patients with the LQTS, especially those with VF. The change in delay is abrupt in the LQTS, indicating sudden block to activation creating a dynamic substrate for arrhythmogenesis.

Sudden death in noncoronary heart disease is associated with delayed paced ventricular activation.

BACKGROUND: Slowed or delayed myocardial activation and dispersed refractoriness predispose to reentrant excitation that may lead to ventricular fibrillation (VF). Increased ventricular electrogram duration (DeltaED) in response to extrastimuli and increased S1S2 coupling intervals at which electrogram duration starts to increase (S1S2delay) are seen both in hypertrophic cardiomyopathy (HCM) in those at risk of VF and in patients with idiopathic VF (IVF). METHODS AND RESULTS: DeltaED and S1S2delay have been measured using paced electrogram fractionation analysis in 266 patients with noncoronary heart disease. Of these, one group of 61 patients had a history of VF and included 21 HCM, 17 IVF, 13 long-QT syndrome (LQTS), 5 dilated cardiomyopathy (DCM), and 5 others. These were compared with 205 patients with similar diseases with no VF history (non-VF group) and a control group (n=12) without heart disease. Results from HCM VF patients (DeltaED, 19+/-3.3 ms; S1S2delay, 350+/-9.7 ms) differed sharply from observations in HCM non-VF patients (DeltaED, 7.3+/-1.35 ms; S1S2delay, 312+/-6.7 ms; P<0.001). DCM VF patients had longer delays (DeltaED, 14.3+/-5.9; S1S2delay, 344+/-11.2) than DCM non-VF patients (DeltaED, 5.8+/-1.87 ms; S1S2delay, 311+/-5.7 ms; P<0.001), with major differences also seen comparing LQTS VF (DeltaED, 12.4+/-5.3 ms; S1S2delay, 343+/-13.8 ms) and LQTS non-VF patients (DeltaED, 11.0+/-2.7 ms; S1S2delay, 320+/-5.4 ms; P<0.001). IVF patients had both severely abnormal and normal areas of myocardium. CONCLUSIONS: Slowed or delayed myocardial activation is a common feature in patients with noncoronary heart disease with a history of VF, and its assessment may allow the prospective prediction of VF risk in these patients.

An extended computational model of the circulatory system for designing ventricular assist devices.

An extended computational model of the circulatory system has been developed to predict blood flow in the presence of ventricular assist devices (VADs). A novel VAD, placed in the descending aorta, intended to offload the left ventricle (LV) and augment renal perfusion is being studied. For this application, a better understanding of the global hemodynamic response of the VAD, in essence an electrically driven pump, and the cardiovascular system is necessary. To meet this need, a model has been established as a nonlinear, lumped-parameter electrical analog, and simulated results under different states [healthy, congestive heart failure (CHF), and postinsertion of VAD] are presented. The systemic circulation is separated into five compartments and the descending aorta is composed of three components to accurately yield the system response of each section before and after the insertion of the VAD. Delays in valve closing time and blood inertia in the aorta were introduced to deliver a more realistic model. Pump governing equations and optimization are based on fundamental theories of turbomachines and can serve as a practical initial design point for rotary blood pumps. The model's results closely mimic established parameters for the circulatory system and confirm the feasibility of the intra-aortic VAD concept. This computational model can be linked with models of the pump motor to provide a valuable tool for innovative VAD design.

Numerical simulation of paced electrogram fractionation: relating clinical observations to changes in fibrosis and action potential duration.

UNLABELLED: Simulating paced electrogram fractionation. INTRODUCTION: Paced electrogram fractionation analysis (PEFA) may identify a re-entrant substrate in patients at risk of ventricular fibrillation (VF) by detecting prolonged, fractionated ventricular electrograms ("fractionation") in response to premature extrastimuli. Numerical simulations of action potential (AP) propagation through human myocardium following such premature stimulation were performed to study the relationship between electrogram fractionation, fibrosis, and changes in AP currents. METHODS AND RESULTS: Activation in a resistive monodomain 2 cm2 sheet of myocardium containing nonconducting fibrous tissue was modeled using standard numerical methods for solutions of partial differential equations using the Priebe-Beukelmann (PB) AP equations. Myocardial fibrosis significantly influenced electrogram morphology. High densities of closely spaced fibrous septa caused functional block and altered propagation paths at short coupling intervals, and produced large increases in electrogram duration similar to those associated with increased risk of VF in clinical studies. Prolongation of the cardiac AP using the heart failure variant of the PB model further increased the amount of fractionation and thereby replicated clinical recordings more closely than did fibrosis alone. Increasing AP dispersion by a variable reduction in the potassium current I(Kr) simulated results seen in patients with the long QT syndrome with an abrupt increase in electrogram duration, while a uniform reduction in I(Kr) alone did not result in fractionated electrograms. In contrast, increases in cytosolic Ca2+ and Ca2+ buffering by troponin to simulate HCM had little effect on fractionation. CONCLUSIONS: These results relate the effects of fibrosis, AP abnormalities, and dispersion of AP duration to the characteristic electrograms recorded in patients at risk of sudden death.

Electrogram prolongation and nifedipine-suppressible ventricular arrhythmias in mice following targeted disruption of KCNE1.

Mutations in KCNE1, the gene encoding the beta subunit of the slowly activating delayed rectifier potassium current (IKs) channel protein, may lead to the long QT syndrome (LQTS), a condition associated with enhanced arrhythmogenesis. Mice with homozygous deletion of the coding sequence of KCNE1 have inner ear defects strikingly similar to those seen in the corresponding human condition. The present study demonstrated and assessed the mechanism of ventricular arrhythmias in Langendorff-perfused whole heart preparations from homozygous KCNE1-/- mice compared to wild-type mice of the same age. The effects of programmed electrical stimulation with decremental pacing from the basal right ventricular epicardial surface upon electrogram waveforms recorded from the basal left ventricle were assessed and quantified using techniques of paced electrogram fractionation analysis for the first time in an experimental system. All KCNE1-/-(n = 10) but not wild-type (n = 14) mouse hearts empirically demonstrated marked pacing-induced ventricular arrhythmogenicity. This correlated with significant increases in electrogram dispersion, consistent with a wider spread in conduction velocities, in parallel with clinical findings from LQTS patients with potassium channel mutations. In contrast, introduction of 100 nM isoprenaline induced arrhythmogenicity in both KCNE1-/- (n = 7) and wild-type (n = 6) hearts during pacing. Furthermore, pretreatment with 1 muM nifedipine exerted a strong anti-arrhythmic effect in the KCNE1-/- hearts (n = 12) that persisted even in the presence of 100 nM isoprenaline (n = 6). Our findings associate KCNE1-/- with an arrhythmogenic phenotype that shows an increased dispersion of conduction velocities, and whose initiation is prevented by nifedipine, a finding that in turn may have therapeutic applications in conditions such as LQTS.

Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a.

Voltage-gated sodium channels drive the initial depolarization phase of the cardiac action potential and therefore critically determine conduction of excitation through the heart. In patients, deletions or loss-of-function mutations of the cardiac sodium channel gene, SCN5A, have been associated with a wide range of arrhythmias including bradycardia (heart rate slowing), atrioventricular conduction delay, and ventricular fibrillation. The pathophysiological basis of these clinical conditions is unresolved. Here we show that disruption of the mouse cardiac sodium channel gene, Scn5a, causes intrauterine lethality in homozygotes with severe defects in ventricular morphogenesis whereas heterozygotes show normal survival. Whole-cell patch clamp analyses of isolated ventricular myocytes from adult Scn5a(+/-) mice demonstrate a approximately 50% reduction in sodium conductance. Scn5a(+/-) hearts have several defects including impaired atrioventricular conduction, delayed intramyocardial conduction, increased ventricular refractoriness, and ventricular tachycardia with characteristics of reentrant excitation. These findings reconcile reduced activity of the cardiac sodium channel leading to slowed conduction with several apparently diverse clinical phenotypes, providing a model for the detailed analysis of the pathophysiology of arrhythmias.