Etienne Pruvot

Repolarization Alternans Reveals Vulnerability to Human Atrial Fibrillation

Background— The substrates for human atrial fibrillation (AF) are poorly understood, but involve abnormal repolarization (action potential duration [APD]). We hypothesized that beat-to-beat oscillations in APD may explain AF substrates, and why vulnerability to AF forms a spectrum from control subjects without AF to patients with paroxysmal then persistent AF. Methods and Results— In 33 subjects (12 with persistent AF, 13 with paroxysmal AF, and 8 controls without AF), we recorded left (n=33) and right (n=6) atrial APD on pacing from cycle lengths 600 to 500 ms (100 to 120 bpm) up to the point where AF initiated. Action potential duration alternans required progressively faster rates for patients with persistent AF, patients with paroxysmal AF, and controls (cycle length 411±94 versus 372±72 versus 218±33 ms; P<0.01). In AF patients, APD alternans occurred at rates as slow as 100 to 120 bpm, unrelated to APD restitution (P>0.10). In this milieu, spontaneous ectopy initiated AF. At fast rates, APD alternans disorganized to complex oscillations en route to AF. Complex oscillations also arose at progressively faster rates for persistent AF, paroxysmal AF, and controls (cycle length: 316±99 versus 266±19 versus 177±16 ms; P=0.02). In paroxysmal AF, APD oscillations amplified before AF (P<0.001). In controls, APD alternans arose only at very fast rates (cycle length <250 ms; P<0.001 versus AF groups) just preceding AF. In 4 AF patients in whom rapid pacing did not initiate AF, APD alternans arose transiently then extinguished. Conclusions— Atrial APD alternans reveals dynamic substrates for AF, arising most readily (at lower rates and higher magnitudes) in persistent AF then paroxysmal AF, and least readily in controls. APD alternans preceded all AF episodes and was absent when AF did not initiate. The cellular mechanisms for APD alternans near resting heart rates require definition.

Study of atrial arrhythmias in a computer model based on magnetic resonance images of human atria.

The maintenance of multiple wavelets appears to be a consistent feature of atrial fibrillation (AF). In this paper, we investigate possible mechanisms of initiation and perpetuation of multiple wavelets in a computer model of AF. We developed a simplified model of human atria that uses an ionic-based membrane model and whose geometry is derived from a segmented magnetic resonance imaging data set. The three-dimensional surface has a realistic size and includes obstacles corresponding to the location of major vessels and valves, but it does not take into account anisotropy. The main advantage of this approach is its ability to simulate long duration arrhythmias (up to 40 s). Clinically relevant initiation protocols, such as single-site burst pacing, were used. The dynamics of simulated AF were investigated in models with different action potential durations and restitution properties, controlled by the conductance of the slow inward current in a modified Luo-Rudy model. The simulation studies show that (1) single-site burst pacing protocol can be used to induce wave breaks even in tissue with uniform membrane properties, (2) the restitution-based wave breaks in an atrial model with realistic size and conduction velocities are transient, and (3) a significant reduction in action potential duration (even with apparently flat restitution) increases the duration of AF. (c) 2002 American Institute of Physics.

Heart Rate Dynamics at the Onset of Ventricular Tachyarrhythmias as Retrieved From Implantable Cardioverter-Defibrillators in Patients With Coronary Artery Disease

BACKGROUND The recent availability of implantable cardioverter-defibrillators (ICDs) that record 1024 R-R intervals preceding a ventricular tachyarrhythmia (VTA) provides a unique opportunity to analyze heart rate variability (HRV) before the onset of VTA. METHODS AND RESULTS Fifty-eight post-myocardial infarction patients with an implanted ICD for recurrent VTA provided 2 sets of 98 heart rate recordings in sinus rhythm: (1) before a VTA and (2) during control conditions. Three subgroups were considered according to the antiarrhythmic (AA) drug regimen. A state of sympathoexcitation was suggested by the significant reduction in HRV before VTA onset compared with control conditions. beta-Blockers and dl-sotalol enhanced HRV in control recordings; nevertheless, HRV declined before VTA independent of AA drugs. A gradual increase in heart rate and decrease in sinus arrhythmia at VTA onset were specific findings of patients who received dl-sotalol. CONCLUSIONS The peculiar heart rate dynamics observed before VTA onset are suggestive of a state of sympathoexcitation that is independent of AA drugs.

A numerical scheme for modeling wavefront propagation on a monolayer of arbitrary geometry

The majority of models of wavefront propagation in cardiac tissue have assumed relatively simple geometries. Extensions to complicated three-dimensional (3-D) representations are computationally challenging due to issues related both to problem size and to the correct implementation of flux conservation. In this paper, we present a generalized finite difference scheme (GDFS) to simulate the reaction-diffusion system on a 3-D monolayer of arbitrary shape. GDFS is a vertex-centered variant of the finite-volume method that ensures local flux conservation. Owing to an effectively lower dimensionality, the overall computation time is reduced compared to full 3-D models at the same spatial resolution. We present the theoretical background to compute both the wavefront conduction and local electrograms using a matrix formulation. The same matrix is used for both these quantities. We then give some results of simulation for simple monolayers and complex monolayers resembling a human atria.

Autonomic Imbalance Assessed by Heart Rate Variability Analysis in Vasovagal Syncope

In this prospective study, the autonomic modulation of the sinus node of 12 patients (mean age 28 ± 7 years) suffering from vasovagal syncope (VVS) was compared to that of 11 sex and age matched control patients (mean age 32 ± 4 years) by analysis of heart rate variability. Spectral indices (low frequency power [Plf], high frequency power [Phf], total power [Pt], sympathovagal balance [LF/HF]) and temporal indices, the mean of all coupling intervals between normal beats (mRR), the standard deviation about the mean (sdRR), the percentage of adjacent R to R intervals differing by more than 50 msec (pNN50), and the root mean square of variations in successive R to R intervals (rMSSD) were compared at baseline and during head‐up tilt between and within groups. Baseline results were similar in both groups. During tilt testing, comparison of results between groups revealed only significantly higher sdRR and rMSSD and lower LF/HF ratio in VVS patients. Within WS patients, comparison of temporal and spectral analysis between baseline and tilt showed a significant increase of most indices (Plf, Phf, Pt, sdRR, and rMSSD) but a comparable LF/HF ratio; in contrast, control patients exhibited only a significant increase of LF/ HF ratio. In conclusion. VVS patients who developed vasovagal syncope during head‐up tilt demonstrated a nonreciprocal modulation of the sinus node by the autonomic nervous system indicative of a pronounced physiological sympathetic surge along with a paradoxical vagal input to the cardiovascular system.

Analyses of a novel SCN5A mutation (C1850S): conduction vs. repolarization disorder hypotheses in the Brugada syndrome.

AIMS Brugada syndrome (BrS) is characterized by arrhythmias leading to sudden cardiac death. BrS is caused, in part, by mutations in the SCN5A gene, which encodes the sodium channel alpha-subunit Na(v)1.5. Here, we aimed to characterize the biophysical properties and consequences of a novel BrS SCN5A mutation. METHODS AND RESULTS SCN5A was screened for mutations in a male patient with type-1 BrS pattern ECG. Wild-type (WT) and mutant Na(v)1.5 channels were expressed in HEK293 cells. Sodium currents (I(Na)) were analysed using the whole-cell patch-clamp technique at 37 degrees C. The electrophysiological effects of the mutation were simulated using the Luo-Rudy model, into which the transient outward current (I(to)) was incorporated. A new mutation (C1850S) was identified in the Na(v)1.5 C-terminal domain. In HEK293 cells, mutant I(Na) density was decreased by 62% at -20 mV. Inactivation of mutant I(Na) was accelerated in a voltage-dependent manner and the steady-state inactivation curve was shifted by 11.6 mV towards negative potentials. No change was observed regarding activation characteristics. Altogether, these biophysical alterations decreased the availability of I(Na). In the simulations, the I(to) density necessary to precipitate repolarization differed minimally between the two genotypes. In contrast, the mutation greatly affected conduction across a structural heterogeneity and precipitated conduction block. CONCLUSION Our data confirm that mutations of the C-terminal domain of Na(v)1.5 alter the inactivation of the channel and support the notion that conduction alterations may play a significant role in the pathogenesis of BrS.

Prevalence and determinants of QT interval prolongation in medical inpatients

Background:  QT interval prolongation carries an increased risk of torsade de pointes and death.

Premature ventricular contraction-induced cardiomyopathy: Related clinical and electrophysiologic parameters.

BACKGROUND Factors associated with premature ventricular contraction-induced cardiomyopathy (PVCi-CMP) remain debated. OBJECTIVE The purpose of this study was to test the correlation of various factors to the presence PVCi-CMP in a large multicenter population. METHODS One hundred sixty-eight consecutive patients referred for ablation of frequent premature ventricular contractions (PVCs) were included. Patients were divided into 2 groups: group 1 with suspected PVCi-CMP (96 patients, ejection fraction 38% ± 10%, left ventricular end-diastolic diameter 62 ± 8 mm, with or without additional structural heart disease); and group 2 (control group, 72 patients with normal ejection fraction and left ventricular dimensions). Various clinical and electrophysiologic parameters were compared between groups. RESULTS In univariate analysis, left ventricular origin of PVC, lack of palpitations, long PVC coupling interval, epicardial origin of the focus, long sinus beat QRS duration, male gender, high PVC burden, presence of polymorphic PVCs, high PVC QRS duration, and older age were significantly related to the presence of PVCi-CMP. In multivariate analysis, only lack of palpitations, PVC burden, and epicardial origin remained significantly and independently correlated with the presence of cardiomyopathy. Even if sinus QRS duration or PVC left ventricular origin were also found independently linked to PVCi-CMP in the whole population, they were no longer correlated when patients with additional heart disease were excluded. CONCLUSION Lack of palpitations, PVC burden, and epicardial origin are independent factors that identify patients prone to developing PVCi-CMP.

Stepwise Evaluation of Unexplained Syncope in a Large Ambulatory Population

Background: Up to 60% of syncopal episodes remain unexplained. We report the results of a standardized, stepwise evaluation of patients referred to an ambulatory clinic for unexplained syncope.

Takotsubo cardiomyopathy and congenital long QT syndrome in a patient with a novel duplication in the Per-Arnt-Sim (PAS) domain of hERG1

rom the *Department of Clinical Research, University of Bern, Bern, Switzerland, School of Pharmaceutical Sciences, niversity of Geneva, University of Lausanne, Geneva, Switzerland, Service of Cardiology, CHUV, Lausanne, witzerland, Clinique Cécil, Lausanne, Switzerland, Forensic Genetics Unit, University Center of Legal Medicine, eneva and Lausanne, Switzerland, and Service of Medical Genetics, CHUV, Lausanne, Switzerland.