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.

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.

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.

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.

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.

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.

Monophasic action potential recordings in humans.

Bridging basic and clinical electrophysiology has been facilitated by monophasic action potential recordings. The electrocardiogram is a useful clinical approach in detecting abnormal repolarization, but falls short in depicting local repolarization details. The MAP waveform is a reflection of local transmembrane action potentials. We hope to convey a basic understanding of monophasic action potential recording and highlight the clinical utility in both ventricular and atrial arrhythmias.

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.

Ventricular fibrillation induced by stretch pulse: implications for sudden death due to commotio cordis.

INTRODUCTION: Nonpenetrating chest wall impact (commotio cordis) may lead to sudden cardiac death due to the acute initiation of ventricular fibrillation (VF). VF may result from sudden stretch during a vulnerable window, which is determined by repolarization inhomogeneity. METHODS: We examined action potential morphologies and VF inducibility in response to sudden myocardial stretch in the left ventricle (LV). In six Langendorff perfused rabbit hearts, the LV was instrumented with a fluid-filled balloon. Increasing volume and pressure pulses were applied at different times of the cardiac cycle. Monophasic action potentials (MAPs) were recorded simultaneously from five LV epicardial sites. Inter-site dispersion of repolarization was calculated in the time and voltage domains. RESULTS: Sudden balloon inflation induced VF when pressure pulses of 208-289 mmHg were applied within a window of 35-88 msec after MAP upstroke, a period of intrinsic increase in repolarization dispersion. During the pressure pulse, MAPs revealed an additional increase in repolarization dispersion (time domain) by 9 +/- 6 msec (P < 0.01). The maximal difference in repolarization levels (voltage domain) between sites increased from 19 +/- 3% to 26 +/- 3% (P < 0.05). Earliest stretch-induced activation was observed near a site with early repolarization, while sites with late repolarization showed delayed activation. CONCLUSIONS: Sudden myocardial stretch can elicit VF when it occurs during a vulnerable window that is based on repolarization inhomogeneity. Stretch pulses applied during this vulnerable window can lead to nonuniform activation. Repolarization dispersion might play a crucial role in the occurrence of fatal tachyarrhythmias during commotio cordis.

Alternans of atrial action potentials during atrial flutter as a precursor to atrial fibrillation.

BACKGROUND: The mechanisms underlying the transition of typical atrial flutter (Afl) to fibrillation (AF) remain unclear. We set out to test the hypothesis that Afl disorganizes to AF via alternans of atrial action potentials. METHODS AND RESULTS: In 38 patients with Afl, monophasic action potentials (MAPs) were recorded at the isthmus and either high or low right atrium (HRA, LRA) during overdrive pacing to 160 ms or to the initiation of AF, whichever came first. MAP duration measured at 90% repolarization was longer at the isthmus in all patients, and failed to shorten with rate, compared with the HRA (n=38) or LRA (n=5). In 20 patients who developed AF, progressive pacing first caused alternans of isthmus MAP duration and amplitude at mean cycle length of 219+/-45 ms, followed by AF at a mean onset cycle length of 184+/-38 ms. Subsets of this group showed spontaneous action potential duration alternans at the isthmus (11 of 20 patients) and 2:1 isthmus conduction block immediately preceding AF (4 of 20 patients). In the 18 patients who did not develop AF, MAP alternans was less common (9 of 18 patients; P<0.0003), and occurred only at faster pacing (cycle length=169+/-25 ms; P<0.05). CONCLUSIONS: In patients with typical Afl, action potential duration rate maladaptation at the isthmus may lead to action potential duration alternans and conduction block preceding the transition to AF. These isthmus characteristics may enable the spontaneous initiation of AF through wavefront fractionation and may explain the benefits of isthmus ablation in preventing AF recurrence.

Analysis of T-wave morphology from the 12-lead electrocardiogram for prediction of long-term prognosis in male US veterans.

BACKGROUND: The aim of the present study was to assess the prognostic value of novel repolarization descriptors from the 12-lead ECG in a large cohort of US veterans. METHODS AND RESULTS: Male US veterans (n=813) with cardiovascular disease had digital 12-lead ECGs recorded at the VA Medical Center, Washington, DC, between 1984 and 1991. The patient series was retrospectively compiled in 1991; follow-up was prospectively assessed until 2000. Novel ECG variables characterizing repolarization and the T-wave loop were automatically analyzed. Of 772 patients with technically analyzable data, 252 patients (32.6%) died after a mean follow-up of 10.4 +/- 3.8 years. Direct comparison between dead and alive patients showed that the so-called T-wave residua (the absolute and relative amount of nondipolar contents within the T wave) predicted mortality (111 900 +/- 164 700 versus 85 600 +/- 144 800 between dead and alive patients, P<0.0002; and 0.43 +/- 0.62% versus 0.33 +/- 0.56%, P<0.0005 for the absolute and relative T-wave residuum, respectively). On Cox regression analysis entering age, left ventricular ejection fraction, echocardiographic left ventricular hypertrophy, and either of the T-wave residua, risk prediction was independent for the absolute (P=0.022) and for the relative (P=0.006) T-wave residuum, respectively, with age (P<0.0001), presence of left ventricular hypertrophy (P=0.002), and left ventricular ejection fraction (P=0.004) also being predictors of survival. CONCLUSIONS: The heterogeneity of myocardial repolarization, measured by the so-called T-wave residuum in the ECG, confers long-term independent prognostic information in US veterans with cardiovascular disease.

Sodium-hydrogen exchange inhibition during ventricular fibrillation: Beneficial effects on ischemic contracture, action potential duration, reperfusion arrhythmias, myocardial function, and resuscitability.

BACKGROUND: Inhibition of the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1) is emerging as a promising novel strategy for ameliorating myocardial injury associated with ischemia and reperfusion. We investigated whether NHE-1 inhibition (with cariporide) could minimize mechanical and electrical myocardial abnormalities that develop during ventricular fibrillation (VF) and improve outcome using a porcine model of closed-chest resuscitation. METHODS AND RESULTS: Two groups of 8 pigs each were subjected to 8 minutes of untreated VF and randomized to receive either a 3-mg/kg bolus of cariporide or 0.9% NaCl immediately before an 8-minute interval of conventional closed-chest resuscitation. Cariporide prevented progressive increases in left ventricular free-wall thickness (from 1.0+/-0.2 to 1.5+/-0.3 cm with NaCl, P<0.001 versus 0.9+/-0.1 to 1.1+/-0.3 cm with cariporide, P=NS), maintained the coronary perfusion pressure above resuscitability thresholds (10+/-8 versus 19+/-3 mm Hg before attempting defibrillation, P<0.05), and increased resuscitability (2 of 8 versus 8 of 8, P<0.005). In 2 additional groups of 4 pigs each subjected to a briefer interval of untreated VF, cariporide ameliorated postresuscitation shortening of the action potential duration (APD) at 30%, 60%, and 90% repolarization (ie, APD60 at 2 minutes after resuscitation; 75+/-29 versus 226+/-16 ms, P<0.05), minimized postresuscitation ventricular ectopic activity preventing recurrent VF, and lessened postresuscitation myocardial dysfunction. CONCLUSIONS: NHE-1 inhibition may represent a highly potent novel strategy for resuscitation from VF that can ameliorate myocardial manifestations of ischemic injury and improve the effectiveness and outcome of closed-chest resuscitation.

Upstream stimulation versus downstream stimulation: arrhythmogenesis based on repolarization dispersion in the human heart.

OBJECTIVE: The purpose of this study was to test the hypothesis that a ventricular tachycardia (VT) induction site has a shorter action potential duration (APD) and effective refractory period (ERP) than a noninducing site, resulting in collision against longer ERP ("upstream") as opposed to shorter ERP ("downstream," no collision). BACKGROUND: Induction of sustained VT is often feasible at one stimulation site while application of an identical pacing protocol to another site fails to provoke VT. METHODS: Sixty-nine patients undergoing programmed stimulation for VT inducibility had monophasic action potential recording/pacing catheters placed in the right ventricular outflow tract (RVOT) and right ventricular apex (RVA) simultaneously. Up to three extra-stimuli were introduced in 5 to 10 ms decrements until ERP was reached. Upon completion of a drive cycle at one stimulation site, it was repeated at the other. RESULTS: Thirty-eight patients had inducible VT, nine exclusively by RVA pacing and nine exclusively by RVOT pacing. Action potential duration and ERP at the induction site were significantly shorter (12 +/- 15 ms, p <0.05 and 22 +/- 14 ms, p < 0.01, respectively, at 600 ms basic cycle length) than at the noninduction site. Dispersion of repolarization between corresponding APD at the two sites was 58 +/- 41 ms during baseline stimulation (S1) at the inducing site but only 37 +/- 23 ms at the noninducing site (p < 0.05). Dispersion increased during extra-stimulus application (p < 0.05), reaching a maximum of 75 +/- 45 ms during VT induction, but only 53 +/- 33 ms during extra-stimulation at the noninduction site. CONCLUSIONS: Site specificity of VT induction underscores the role of dispersion of repolarization and refractoriness in facilitating re-entry arrhythmias. Upstream stimulation at a site with short repolarization produces larger dispersion and facilitates VT induction.

Mechano-electrical feedback underlying arrhythmias: the atrial fibrillation case.

Mechanoelectrical feedback (MEF) has become firmly established as a mechanism in which mechanical forces experienced by myocardial tissue or cell membranes convey alterations in electrophysiologic characteristics of such tissue. Observations to date mainly concern mechanically induced changes in action potential duration, resting and active potential amplitude, enhanced pacemaker frequency, or afterdepolarizations. While some of these changes (i.e. after depolarizations) may give rise to premature beats, a role of MEF in explaining sustained ventricular tachyarrhythmias has so far been elusive. Here, we review recent findings showing that acute atrial dilatation facilitates atrial fibrillation (AF) and that two stretch-activated channel (SAC) blockers (gadolinium and GsMTx-4) are able to suppress stretch-facilitated AF. These findings strongly support a role of MEF and SACs in promoting sustained arrhythmias and point to a new class of antiarrhythmic drugs.

Electrophysiological effects of flecainide and sotalol in the human atrium during persistent atrial fibrillation.

AIMS: Atrial fibrillation (AF) shortens the atrial action potential and the atrial refractory period. These changes promote persistence of AF. Pharmacological prolongation of atrial action potential duration (APD) may therefore help to prevent recurrent AF. In addition to prolonging APD, sodium channel blockers may prevent AF by inducing post-repolarization refractoriness (PRR). We studied whether two antiarrhythmic drugs (sotalol, flecainide) prolong APD or induce PRR in the fibrillating human atrium. METHODS: In 12 patients with persistent AF (11 male, 58 +/- 5 yrs, 27 +/- 7 months duration of AF), we recorded monophasic action potentials from the right atrial appendage and inferior right atrium at baseline and 15 minutes after intravenous administration of sotalol (1.5 mg/kg) or flecainide (2 mg/kg). APD and effective refractory periods (ERP) were determined. RESULTS: Both drugs prolonged APD90 during AF (flecainide from 109 +/- 7 ms to 137 +/- 10 ms, sotalol from 108 +/- 6 ms to 131 +/- 8 ms, both p < 0.05 vs. baseline). Sotalol prolonged ERP in parallel to APD (from 119 +/- 8 ms to 139 +/- 8 ms, p < 0.05). Flecainide induced PRR by prolonging ERP more than APD90 (from 134 +/- 9 ms to 197 +/- 28 ms, p < 0.05 vs. baseline and vs. sotalol). CONCLUSIONS: Flecainide and sotalol prolong the atrial action potential during atrial fibrillation in humans. In addition, flecainide induces atrial PRR. These electrophysiological effects may reduce AF recurrences and prevent their persistence.

Effect of pacing and mexiletine on dispersion of repolarisation and arrhythmias in DeltaKPQ SCN5A (long QT3) mice.

OBJECTIVE: It has been suggested that both pacing and treatment with mexiletine may reduce torsade de pointes (TdP) arrhythmias in patients with long QT syndrome 3 (LQT3), but it is not fully understood how these interventions could prevent TdP. We therefore studied the effects of pacing and mexiletine in mice with a heterozygous knock-in DeltaKPQ SCN5A(Delta/+) deletion (SCN5A-Tg), a murine LQT3 model. METHODS: Three right and left ventricular monophasic action potentials (MAPs) were simultaneously recorded in Langendorff-perfused hearts of SCN5A-Tg and wild type (WT) littermates. AV block was induced, and pacing was performed at baseline and during mexiletine infusion (4 microg/ml). MAP recordings were analysed for action potential duration (APD), APD dispersion, and early afterdepolarisations (EADs) and related to spontaneous arrhythmias. RESULTS: After inducing AV block, SCN5A-Tg hearts were bradycardic [SCN5A-Tg 532+/-60 vs. WT 284+/-48 ms cycle length (CL, mean+/-S.E.M., P<0.05(*))]. EADs occurred in 16/18, and polymorphic ventricular tachycardia (pVT) in 11/18 SCN5A-Tg but not in 19 WT. SCN5A-Tg had longer APD than WT hearts*. At CL of 200 ms and longer, APD dispersion was higher in SCN5A-Tg [dispersion (APD70): 12+/-3 ms vs. 5+/-2 ms at CL=200 ms*], and increased to 35+/-4 ms* directly prior to pVT episodes. Sudden rate accelerations initially increased APD dispersion due to EADs and APD alternans in SCN5A-Tg, but pacing then reduced APD dispersion. Pacing suppressed (n=9/9) and prevented (n=49/50) pVT. Mexiletine shortened APD at long CL*, and suppressed pVT (n=4/5*), but did not prevent pVT during normal rhythm. CONCLUSIONS: Bradycardia, increased dispersion of APD and EADs provoke ventricular ectopy and pVT in SCN5A-Tg hearts. Ventricular pacing reduces APD dispersion, suppresses EADs and prevents pVT in SCN5A-Tg hearts. These effects provide a pathophysiological rationale for pacing in LQT3.

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.