Amiodarone prevents wave front-tail interactions in patients with heart failure: an in silico study.

Amiodarone (AM) is an antiarrhythmic drug whose chronic use has proved effective in preventing ventricular arrhythmias in a variety of patient populations, including those with heart failure (HF). AM has both class III [i.e., it prolongs the action potential duration (APD) via blocking potassium channels) and class I (i.e., it affects the rapid sodium channel) properties; however, the specific mechanism(s) by which it prevents reentry formation in patients with HF remains unknown. We tested the hypothesis that AM prevents reentry induction in HF during programmed electrical stimulation (PES) via its ability to induce postrepolarization refractoriness (PRR) via its class I effects on sodium channels. Here we extend our previous human action potential model to represent the effects of both HF and AM separately by calibrating to human tissue and clinical PES data, respectively. We then combine these models (HF + AM) to test our hypothesis. Results from simulations in cells and cables suggest that AM acts to increase PRR and decrease the elevation of takeoff potential. The ability of AM to prevent reentry was studied in silico in two-dimensional sheets in which a variety of APD gradients (ΔAPD) were imposed. Reentrant activity was induced in all HF simulations but was prevented in 23 of 24 HF + AM models. Eliminating the AM-induced slowing of the recovery of inactivation of the sodium channel restored the ability to induce reentry. In conclusion, in silico testing suggests that chronic AM treatment prevents reentry induction in patients with HF during PES via its class I effect to induce PRR.NEW & NOTEWORTHY This work presents a new model of the action potential of the human, which reproduces the complex dynamics during premature stimulation in heart failure patients with and without amiodarone. A specific mechanism of the ability of amiodarone to prevent reentrant arrhythmias is presented.

QRS micro-fragmentation as a mortality predictor.

AIMS: Fragmented QRS complex with visible notching on standard 12-lead electrocardiogram (ECG) is understood to represent depolarization abnormalities and to signify risk of cardiac events. Depolarization abnormalities with similar prognostic implications likely exist beyond visual recognition but no technology is presently suitable for quantification of such invisible ECG abnormalities. We present such a technology. METHODS AND RESULTS: A signal processing method projects all ECG leads of the QRS complex into optimized three perpendicular dimensions, reconstructs the ECG back from this three-dimensional projection, and quantifies the difference (QRS 'micro'-fragmentation, QRS-µf) between the original and reconstructed signals. QRS 'micro'-fragmentation was assessed in three different populations: cardiac patients with automatic implantable cardioverter-defibrillators, cardiac patients with severe abnormalities, and general public. The predictive value of QRS-µf for mortality was investigated both univariably and in multivariable comparisons with other risk factors including visible QRS 'macro'-fragmentation, QRS-Mf. The analysis was made in a total of 7779 subjects of whom 504 have not survived the first 5 years of follow-up. In all three populations, QRS-µf was strongly predictive of survival (P < 0.001 univariably, and P < 0.001 to P = 0.024 in multivariable regression analyses). A similar strong association with outcome was found when dichotomizing QRS-µf prospectively at 3.5%. When QRS-µf was used in multivariable analyses, QRS-Mf and QRS duration lost their predictive value. CONCLUSION: In three populations with different clinical characteristics, QRS-µf was a powerful mortality risk factor independent of several previously established risk indices. Electrophysiologic abnormalities that contribute to increased QRS-µf values are likely responsible for the predictive power of visible QRS-Mf.

A model for human action potential dynamics in vivo.

Computational modeling based on experimental data remains an important component in cardiac electrophysiological research, especially because clinical data such as human action potential (AP) dynamics are scarce or limited by practical or ethical concerns. Such modeling has been used to develop and test a variety of mechanistic hypotheses, with the majority of these studies involving the rate dependence of AP duration (APD) including APD restitution and conduction velocity (CV). However, there is very little information regarding the complex dynamics at the boundary of repolarization (or refractoriness) and reexcitability. Here, we developed a "minimal" ionic model of the human AP, based on in vivo human monophasic AP (MAP) recordings obtained during clinical programmed electrical stimulation (PES) to address the progressive decrease in AP take-off potential (TOP) and associated CV slowing seen during three tightly spaced extrastimuli. Recent voltage-clamp data demonstrating the effect of intracellular calcium on sodium current availability were incorporated and were required to reproduce large (>15 mV) elevations in take-off potential and progressive encroachment. Introducing clinically observed APD gradients into the model enabled us to replicate the dynamic response to PES in patients leading to conduction block and reentry formation for the positive, but not the negative, APD gradient. Finally, we modeled the dynamics of reentry and show that spiral waves follow a meandering trajectory with a period of ~180 ms. We conclude that our model reproduces a variety of electrophysiological behavior including the response to sequential premature stimuli and provides a basis for studies of the initiation of reentry in human ventricular tissue.NEW & NOTEWORTHY This work presents a new model of the action potential of the human which reproduces the complex dynamics during premature stimulation in patients.

Rhythmic Aortic Contractions Induced by Electrical Stimulation In Vivo in the Rat.

For over a century, the behavior of the aorta and other large arteries has been described as passive elastic tubes in which no active contraction occurs in the smooth muscle wall. In response to pulsatile pressure changes, the vessels undergo a 'passive' elastic dilatation-contraction cycle, described as a "Windkessel" effect. However, Mangel and colleagues have presented evidence that is contrary to this view. They reported that in the rabbit, the aorta undergoes rhythmic 'active' (contraction) during the cardiac cycle; but these findings have been largely ignored. In the present study, we observed spontaneous contractions in synchrony with the heartbeat in another species (rat). In addition we demonstrate that aorta contractions are of neurogenic origin. Electrical stimulation of the aorta evoked contractions that occur at a rate that is in the range of the animal's heartbeat and are suppressed by tetrodotoxin and the alpha-adrenergic receptor blocker, phentolamine. Altogether, these findings indicate that aortic contractions are under neural control from the heart.

Drug-induced post-repolarization refractoriness as an antiarrhythmic principle and its underlying mechanism.

AIMS: We hypothesized that amiodarone (AM), unlike d-sotalol (DS) (a 'pure' Class III agent), not only prolongs the action potential duration (APD) but also causes post-repolarization refractoriness (PRR), thereby preventing premature excitation and providing superior antiarrhythmic efficacy. METHODS AND RESULTS: We tested this hypothesis in 31 patients with inducible ventricular tachycardia (VT) during programmed stimulation with the use of the 'Franz' monophasic action potential (MAP) catheter with simultaneous pacing capability. We determined the effective refractory period (ERP) for each of three extrastimuli (S2-S4) and the corresponding MAP duration at 90% repolarization (APD90), both during baseline and on randomized therapy with either DS (n = 15) or AM (n = 16). We defined ERP > APD90 as PRR and ERP < APD90 as 'encroachment' on repolarization. A revised computer action potential model was developed to help explain the mechanisms of these in-vivo human-heart phenomena. Encroachment but not PRR was present in all patients at baseline and during DS treatment (NS vs. baseline), and VT was non-inducible in only 2 of 15 DS patients. In contrast, in 12 of 16 AM patients PRR was present (P < 0.001 vs. baseline), and VT was no longer inducible. Our model (with revised sodium channel kinetics) reproduced encroachment and drug-induced PRR. CONCLUSION: Both, AM and DS, prolonged APD90 but only AM produced PRR and prevented encroachment of premature extrastimuli. Our computer simulations suggest that PRR is due to altered kinetics of the slow inactivation of the rapid sodium current. This may contribute to the high antiarrhythmic efficacy of AM.

The role of action potential alternans in the initiation of atrial fibrillation in humans: a review and future directions.

This review highlights the role of atrial monophasic action potential duration (APD) in understanding atrial electrical properties in paroxysmal, persistent, and permanent atrial fibrillation (AF) states. Alternans of APD and rate maladaptation in a spatially divergent way appear mechanistically involved in AF initiation, development, and persistence. The underlying pathophysiology warrants further investigation.

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.

Intrathoracic impedance preceding ventricular tachyarrhythmia episodes.

BACKGROUND: Heart failure is associated with ventricular tachyarrhythmias (VT/VF). Fluid accumulation during worsened heart failure may trigger VT/VF. Increased intrathoracic impedance has been correlated with fluid accumulation during heart failure. Implanted defibrillators capable of daily measures of intrathoracic impedance allow correlation of impedance with occurrence of VT/VF. We hypothesized that VT/VF episodes are preceded by decreases in intrathoracic impedance. The goal was to identify the relationship of intrathoracic impedance measured by implanted cardioverter defibrillators to the occurrence of VT/VF. METHOD: Implanted defibrillator follow-up data were obtained retrospectively. Those with Medtronic OptiVol (Medtronic Inc., Minneapolis, MN, USA), storing averaged daily and reference impedance values, were reviewed for VT/VF episodes. Impedance changes in the week leading up to VT/VF were analyzed. RESULTS: A total of 317 VT/VF episodes in a cohort of 121 patients' follow-up data were evaluated. Averaged daily intrathoracic impedance declined preceding 64% of VT/VF episodes, with an average decline of 0.46 +/- 0.35 Ohms from the day before the VT/VF episodes. However, the mean values of the averaged daily and reference impedance did not change significantly. A novel measure, DeltaTI, the sum of the daily differences between the averaged daily and reference impedance, was negative preceding 66% of VT/VF episodes (P < 0.001). The mean DeltaTI was -4.0 +/- 1.3 Ohms, which was significantly lower than the theoretically expected value of zero Ohms (P < 0.01). CONCLUSION: (1) Averaged daily impedance declined preceding 64% of VT/VF episodes, but the overall decline was of small magnitude; (2) a novel measure, DeltaTI, was negative preceding 66% of VT/VF episodes, and significantly below zero.

Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3.

AIMS: Clinical observations in patients with long QT syndrome carrying sodium channel mutations (LQT3) suggest that bradycardia caused by parasympathetic stimulation may provoke torsades de pointes (TdP). Beta-adrenoceptor blockers appear less effective in LQT3 than in other forms of the disease. METHODS AND RESULTS: We studied effects of autonomic modulation on arrhythmias in vivo and in vitro and quantified sympathetic innervation by autoradiography in heterozygous mice with a knock-in deletion (DeltaKPQ) in the Scn5a gene coding for the cardiac sodium channel and increased late sodium current (LQT3 mice). Cholinergic stimulation by carbachol provoked bigemini and TdP in freely roaming LQT3 mice. No arrhythmias were provoked by physical stress, mental stress, isoproterenol, or atropine. In isolated, beating hearts, carbachol did not prolong action potentials per se, but caused bradycardia and rate-dependent action potential prolongation. The muscarinic inhibitor AFDX116 prevented effects of carbachol on heart rate and arrhythmias. beta-Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. Beta-adrenoceptor density was reduced in LQT3 hearts. Acute beta-adrenoceptor blockade by esmolol, propranolol or chronic propranolol in vivo did not suppress arrhythmias. Chronic flecainide pre-treatment prevented arrhythmias (all P < 0.05). CONCLUSION: Cholinergic stimulation provokes arrhythmias in this model of LQT3 by triggering bradycardia. beta-Adrenoceptor density is reduced, and beta-adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and beta-adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current.

Short-term memory and restitution during ventricular fibrillation in human hearts: an in vivo study.

BACKGROUND: Action potential duration (APD) variation is an important determinant of wave break and reentry. The determinants of APD variability during early ventricular fibrillation (VF) in myopathic human hearts have not been studied. The objective of this study was to study the role of APD restitution and short-term cardiac memory on variation in human VF. METHODS AND RESULTS: The study consisted of 7 patients (67+/-9 years old) with ejection fraction <35%. Monophasic action potentials were recorded from the right and/or left ventricular septum during VF. APD(60/90) was measured in sinus beat preceding induction of VF, and its amplitude was used to define 60%/90% repolarization in VF. The monophasic action potential upstroke (dV/dt(max)) was used to characterize local excitability. Simple linear regression showed that variability in APD(n60) was determined by APD/diastolic interval restitution (R(2)=0.48, P<0.0001) and short-term memory (APD(60) n-1, n-2, n-3, n-4; R(2)=0.55, 0.40, 0.33, and 0.27 respectively; P<0.001). Using multiple stepwise regression, short-term memory and restitution accounted for 62% of variance in APD(60) (P<0.001). Individually, memory effect had the greatest contribution to APD variability (R(2)=0.55, P<0.0001). CONCLUSIONS: In early human VF, short-term memory and APD/diastolic interval restitution explain most of the APD variability, with memory effects predominating. This suggests that in early human VF, short-term cardiac memory may provide a novel therapeutic target to modulate progression of VF in myopathic patients.

Management strategies when implanted cardioverter defibrillator leads fail: survey findings.

BACKGROUND: Defibrillator implanters have adopted different approaches to managing failures of multicomponent implanted cardioverter defibrillator (ICD) leads. Although recent publications identified single-component failures as common mechanisms of failure, there are no published data regarding how best to manage these failures. METHODS: An internet-based survey was conducted to identify current management strategies. Questions were asked regarding isolated failure of a high-voltage coil or of a pace/sense electrode, in order to identify the frequency of various techniques to correct these failures. RESULTS: A worldwide query collected strategies from 376 physicians identifying themselves as ICD-implanting physicians. Replies came from 28 countries, with the USA accounting for 83.2%. The survey was completed by 85.6% of respondents. Implant experience was >10 years for 61.1%, 3-10 years for 29.1%, and <3 years for 10.4%. When the right ventricular coil failed, 52% abandoned and 48% explanted the failed lead. In superior vena cava coil failure, 61.2% chose to simply exclude this coil, using the other intact lead components. For pace/sense defects, 53.1% chose to implant a new pace/sense lead or switch sensing electrodes, using the intact lead components. Medical literature (76.1%), personal experience (67.6%), and professional guidelines (63.7%) were strong decision-making influences. CONCLUSIONS: (1) Management decisions for single-component failures of ICD leads are complex; (2) Significant differences in management strategy exist among physicians; (3) Medical literature and professional guidelines are strong influences for these decisions; (4) A lead failure registry could help identify reasons for such differences and help guide management.

Giant T-U waves precede torsades de pointes in long QT syndrome: a systematic electrocardiographic analysis in patients with acquired and congenital QT prolongation.

OBJECTIVES: This study sought to identify electrocardiographic (ECG) criteria that are associated with initiation of torsades de pointes (TdP) in patients with acquired (a-) and congenital (c-) long QT syndrome (LQTS). BACKGROUND: Electrocardiographic criteria used as risk predictors for TdP commonly rely on a prolonged QT interval but rarely consider abnormal T-U waves. METHODS: We analyzed ECG recordings with TdP from 35 LQTS patients (15 c-LQTS and 20 a-LQTS) and compared them with premature ventricular complexes (PVCs) from 40 patients with normal QT intervals and with PVCs in 24 of the 35 LQTS patients not related to TdP. RESULTS: Abnormal T-U waves (6.2 +/- 0.9 mm) directly preceded TdP in 34 of 35 LQTS patients and were larger than T-wave amplitude (2.8 +/- 0.2 mm) in control patients and larger than the largest T-U-wave in LQTS without TdP (4.7 +/- 0.8 mm). The TdP-initiating beat emerged from a T-U-wave in 27 of 35 LQTS patients and in none of 40 control patients. The QRS duration of the first TdP beat (175 +/- 12 ms) was longer than in control PVCs (145 +/- 4 ms) and in PVCs in LQTS patients not related to TdP (138 +/- 22 ms). The QRS angle was less steep before TdP than in other PVCs (all p < 0.05). CONCLUSIONS: Abnormal, giant T-U waves separate TdP initiation in LQTS patients from PVCs in other heart disease and from other PVCs in LQTS patients. These ECG analyses suggest that early afterdepolarizations initiate TdP and, if present, may help to identify an imminent risk for TdP.

Quantifying fractionation and rate in human atrial fibrillation using monophasic action potentials: implications for substrate mapping.

AIMS: To use monophasic action potentials (MAPs) to better assess the rate and the presence of fractionated electrograms during the mapping of atrial fibrillation (AF). Substrate mapping is increasingly central to AF ablation. However, traditional bipolar signals poorly represent waveform shape, making it unclear whether fractionation reflects local waveform variations, true electrogram fragmentation, or noise, and raising issues on whether their spectral dominant frequencies (DFs) accurately estimate AF rate. METHODS AND RESULTS: In 28 patients with paroxysmal or persistent AF (left atrial diameters 44 +/- 8 mm), we studied 49 epochs of right atrial MAPs during AF. We compared fractionation, spectral and time-domain AF rate estimates using MAPs and bipolar electrograms obtained by filtering the MAPs. Fractionation was overestimated in bipolar rather than MAP electrograms (P = 0.005) and often reflected artefacts on the MAPs. Conversely, local waveform variability in the MAPs, including alternans or fractionation, was often uniform in the bipolar electrograms. The measured AF cycle length (CL) was accurately represented by the DF of the MAPs (r = 0.73, P < 0.001) but, due to double counting, not by the DF of bipolar signals (r = 0.29, P = 0.07). Spectral CL estimates were therefore accurate (< or = 20 ms from measured CL) for 77% of MAPs but for 45% of bipolar signals only. A novel autocorrelation method better estimated CL in MAPs (r = 0.92; P < 0.001) and bipoles (r = 0.82; P < 0.001), with 89 and 77% accuracy, respectively (P < 0.01). CONCLUSION: Atrial fibrillation organization and rate are better represented by MAPs, which portray fibrillatory waveform shape, than by bipolar recordings. This approach may more reliably portray electrogram variability, fragmentation, and rate for the mapping of AF substrates.

T-wave alternans, restitution of human action potential duration, and outcome.

OBJECTIVES: Our aim was to study the relationship between T-wave alternans (TWA) and rate-response (restitution) of repolarization in subjects with and without ventricular systolic dysfunction. BACKGROUND: T-wave alternans is a promising predictor of sudden death, yet the mechanisms linking it with human ventricular arrhythmias are unclear. From theoretic considerations, we hypothesized that abnormal TWA is linked with steep restitution of action potential duration (APD) and that both predict arrhythmic outcome. METHODS: We studied 53 subjects with left ventricular ejection fraction (LVEF) < or =40% and 18 control subjects. At electrophysiologic study, we recorded APD at 90% repolarization (APD(90)) in the right (n = 62) or left (n = 9) ventricle during pacing while measuring TWA from the body surface. RESULTS: As expected, TWA (at <109 beats/min) was more likely to be abnormal in study than in control subjects (p < 0.01). However, study (LVEF 28 +/- 8%) and control (LVEF 58 +/- 12%) subjects did not differ in APD(90) restitution slope maxima (1.2 +/- 0.6 vs. 1.3 +/- 0.6, respectively; p = 0.82) or numbers with steep slope (>1; 58% vs. 67%). T-wave alternans and simultaneous APD alternans always occurred at diastolic intervals where APD restitution was not steep (p < 0.001), and there was no relationship between maximum restitution slope and TWA magnitude. Over 829 +/- 473 days, TWA (p = 0.02), but not restitution slope >1, predicted ventricular arrhythmias in subjects with LVEF < or =40%. CONCLUSIONS: The mechanism by which TWA predicts arrhythmic mortality does not reflect the maximum slope of ventricular APD restitution. Better understanding of the mechanisms underlying TWA may enable improved prediction and prevention of ventricular arrhythmias.