Minimum Information about a Cardiac Electrophysiology Experiment (MICEE): standardised reporting for model reproducibility, interoperability, and data sharing.

Cardiac experimental electrophysiology is in need of a well-defined Minimum Information Standard for recording, annotating, and reporting experimental data. As a step towards establishing this, we present a draft standard, called Minimum Information about a Cardiac Electrophysiology Experiment (MICEE). The ultimate goal is to develop a useful tool for cardiac electrophysiologists which facilitates and improves dissemination of the minimum information necessary for reproduction of cardiac electrophysiology research, allowing for easier comparison and utilisation of findings by others. It is hoped that this will enhance the integration of individual results into experimental, computational, and conceptual models. In its present form, this draft is intended for assessment and development by the research community. We invite the reader to join this effort, and, if deemed productive, implement the Minimum Information about a Cardiac Electrophysiology Experiment standard in their own work.

The repolarization-excitability relationship in the human right atrium is unaffected by cycle length, recording site and prior arrhythmias.

OBJECTIVES: The goal of this study was to determine the relationship between repolarization and excitability in the human atrium under various conditions. BACKGROUND: Action potential duration (APD) measurements from monophasic action potential (MAP) recordings provide a surrogate for measuring the effective refractory period (ERP) in human ventricle. The relationship between repolarization and refractoriness in human atrium and the effect of prior atrial fibrillation/flutter on the ERP/APD correlation are unknown. METHODS: Seven patients with sinus rhythm and 15 patients after conversion of atrial flutter or fibrillation were evaluated. Monophasic action potentials were recorded at multiple right atrial sites and during different basic cycle lengths from 300 to 700 ms, while ERPs were determined by extrastimulus technique using the MAP recording-pacing combination catheter. RESULTS: There was a close correlation between ERP and APD at 70% repolarization (APD70, r = 0.97; p < 0.001) and 90% repolarization (APD90, r = 0.98; p < 0.001), respectively. Refractoriness occurred at a repolarization level of 72 +/- 8%. The ERP/APD70 and ERP/APD90 ratios averaged 1.06 +/- 0.10 and 0.86 +/- 0.08, respectively. These ratios were nearly constant over the entire range of basic cycle lengths, between different sites in individual patients and between different patients. Patients cardioverted from atrial fibrillation or flutter exhibited no significant differences in the ERP/APD relationship compared with patients with sinus rhythm. CONCLUSIONS: Effective refractory period and APD are closely related in the human right atrium. Using the MAP recording technique, atrial ERPs can be assessed by measurement of APDs. Effective refractory period is most closely reflected by APD70. Thus, MAP recordings allow investigation of the local activation and repolarization time course beat by beat, visualizing the excitable gap.

Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome.

KCNQ1 encodes KCNQ1, which belongs to a family of voltage-dependent K(+) ion channel proteins. KCNQ1 associates with a regulatory subunit, KCNE1, to produce the cardiac repolarizing current, I(Ks). Loss-of-function mutations in the human KCNQ1 gene have been linked to Jervell and Lange-Nielsen Syndrome (JLNS), a disorder characterized by profound bilateral deafness and a cardiac phenotype. To generate a mouse model for JLNS, we created a line of transgenic mice that have a targeted disruption in the Kcnq1 gene. Behavioral analysis revealed that the Kcnq1(-/-) mice are deaf and exhibit a shaker/waltzer phenotype. Histological analysis of the inner ear structures of Kcnq1(-/-) mice revealed gross morphological anomalies because of the drastic reduction in the volume of endolymph. ECGs recorded from Kcnq1(-/-) mice demonstrated abnormal T- and P-wave morphologies and prolongation of the QT and JT intervals when measured in vivo, but not in isolated hearts. These changes are indicative of cardiac repolarization defects that appear to be induced by extracardiac signals. Together, these data suggest that Kcnq1(-/-) mice are a potentially valuable animal model of JLNS.

Monophasic action potential recordings from intact mouse heart: validation, regional heterogeneity, and relation to refractoriness.

INTRODUCTION: The monophasic action potential (MAP) technique has been validated in humans and larger animals, but, in mice, MAP recordings available to date show little resemblance to the murine ventricular transmembrane action potential (TAP) measured by conventional microelectrodes. We developed a miniaturized MAP contact electrode technique to establish in isolated mouse hearts: (1) optimal electrode size; (2) validation against TAP; (3) relationship between repolarization and refractoriness; and (4) regional repolarization differences. METHODS AND RESULTS: In 30 Langendorff-perfused mouse hearts, MAP electrodes of tip diameter 1.5, 1.0, and 0.25 mm were tested by comparing MAPs and TAPs from epicardial and endocardial surfaces of both ventricles. Only the MAP contact electrode of 0.25-mm tip diameter consistently produced MAP recordings that had wave shapes nearly identical to TAP recordings. MAP durations measured at 30%, 50%, 70%, and 90% repolarization (APD30, APD50, APD70, APD90) highly correlated with TAP measurements (r = 0.97, P < 0.00001). APD50 was significantly longer in endocardial than in epicardial recordings (right ventricle: 9.3+/-1.1 msec vs 3.9+/-1.1 msec; left ventricle: 9.9+/-2.1 msec vs 6.2+/-1.9 msec; both P < 0.001), demonstrating transmural repolarization differences. Effective refractory period (ERP) determined at basic cycle lengths from 70 to 200 msec correlated with 80%+/-6% of total repolarization, with an ERP/APD90 ratio of 0.85+/-0.14. CONCLUSION: Murine myocardial repolarization, regional repolarization heterogeneity, and relation to refractoriness can be assessed reliably by this miniaturized MAP contact electrode technique, which renders action potential wave shapes similar to that of intracellular microelectrodes. This technique may be useful for exploring repolarization abnormalities in genetically altered mice.

Rate-dependence of QT dispersion and the QT interval: comparison of atrial pacing and exercise testing.

OBJECTIVES: The study was done to determine whether variables of QT dispersion from the 12-lead electrocardiogram (ECG) are dependent on heart rate. BACKGROUND: The dispersion of the QT interval is under evaluation as a risk marker in patients at risk for ventricular arrhythmias. Assuming that a similar rate correction is necessary as for the QT interval itself, investigators have frequently reported QTc-dispersion values utilizing the Bazett formula. It is not known whether there is a physiologic basis for such a rate correction in the human heart. METHODS: In 35 patients referred for evaluation of ventricular arrhythmias, digital 12-lead ECGs recorded at various heart rates during submaximal exercise testing and again during atrial pacing upon electrophysiologic testing were submitted to computerized interactive analysis of several ECG dispersion variables. RESULTS: Data from 11 patients were excluded due to incomplete high-quality analysis possible at all heart rates. From the remaining 24 patients, a total of 193 ECG recordings at various heart rates (ranging from 76 +/- 17 beats/min to 117 +/- 14 beats/min during atrial pacing and from 78 +/- 18 beats/min to 110 +/- 14 beats/min during exercise testing) were available. A highly significant linear relationship with heart rate was found for both the QT interval and the Q-to-T-peak interval. By contrast, standard QT interval dispersion (QTmax - QTmin), the T-peak-to-T-end interval, and the average area under the T wave did not change with increasing heart rates. CONCLUSIONS: Dispersion of the QT interval and other ECG variables of dispersion of ventricular repolarization are independent of heart rate. Therefore, it is not necessary to rate-correct these measurements.

Analysis of 12-lead T-wave morphology for risk stratification after myocardial infarction.

BACKGROUND: The stratification of post-myocardial infarction (MI) patients at risk of sudden cardiac death remains important. The aim of the present study was to assess the prognostic value of novel T-wave morphology descriptors derived from resting 12-lead ECGs. METHODS AND RESULTS: In 280 consecutive post-MI patients, a 12-lead ECG was recorded before discharge, optically scanned, and digitized. For the present study, 5 T-wave morphology descriptors were automatically calculated after singular value decomposition of the ECG signal. The total cosine R-to-T (TCRT [describes the global angle between repolarization and depolarization wavefront]) and the T-wave loop dispersion were univariately associated (P:=0.0002 and P:<0.002, respectively, U: test) with 27 prospectively defined clinical events in 261 patients (mean follow-up 32+/-10 months). Kaplan-Meier event probability curves for strata above and below the median confirmed the strong risk discrimination by TCRT and T-wave loop dispersion (P:<0.003 and P:<0.001, respectively, log-rank test). On Cox regression analysis, with the entering of age, left ventricular ejection fraction, heart rate, QRS width, reperfusion therapy, beta-adrenergic-blocker treatment, and standard deviation of R-R intervals on 24-hour Holter monitoring, TCRT (P:<0.03) yielded independent predictive value, whereas T-wave loop dispersion was of borderline independence (P:=0.064). Heart rate (P:<0.02), left ventricular ejection fraction (P:<0.02), and reperfusion therapy (P:<0.02) also remained in the final model. CONCLUSIONS: Computerized T-wave morphology analysis of the 12-lead resting ECG permits independent assessment of post-MI risk and an improved risk stratification when combined with other risk markers.

Gadolinium decreases stretch-induced vulnerability to atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is frequently associated with atrial dilatation caused by pressure or volume overload. Stretch-activated channels (SACs) have been found in myocardial cells and may promote AF in dilated atria. To prove this hypothesis, we investigated the effect of the SAC blocker gadolinium (Gd(3+)) on AF propensity in the isolated rabbit heart during atrial stretch. METHODS AND RESULTS: In 16 isolated Langendorff-perfused rabbit hearts, the interatrial septum was perforated to equalize biatrial pressures. Caval and pulmonary veins were occluded. Intra-atrial pressure (IAP) was increased in steps of 2 to 3 cm H(2)O by increasing the pulmonary outflow fluid column. Vulnerability to AF was evaluated by 15-second burst pacing at each IAP level. At baseline, IAP needed to be raised to 8.8+/-0.2 cm H(2)O (mean+/-SEM) to induce AF. A dose-dependent decrease in AF vulnerability was observed after Gd(3+) 12.5, 25, and 50 micromol/L was added. AF threshold increased to 19.0+/-0.5 cm H(2)O with Gd(3+) 50 micromol/L (P<0.001 versus baseline). Spontaneous runs of AF occurred in 5 hearts on a rise of IAP to 13.8+/-3.3 cm H(2)O at baseline but never during Gd(3+). Atrial effective refractory period shortened progressively from 78+/-3 ms at 0.5 cm H(2)O to 52+/-3 ms at 20 cm H(2)O (P<0.05). Gd(3+) 50 micromol/L had no significant effect on effective refractory period. CONCLUSIONS: Acute atrial stretch significantly enhances the vulnerability to AF. Gd(3+) reduces the stretch-induced vulnerability to AF in a dose-dependent manner. Block of SAC might represent a novel antiarrhythmic approach to AF under conditions of elevated atrial pressure or volume.

Electrophysiological basis of QT dispersion measurements.

Dispersion of ventricular repolarization is a now widely used term describing nonhomogeneous recovery of excitability or heterogeneity of ventricular repolarization. It is usually expressed as the difference or the range of various repolarization measurements obtained from a heart. Experimentally, an increased dispersion of ventricular repolarization was found to be tightly associated with increased propensity for ventricular arrhythmias, and, therefore, is considered an important arrhythmogenic mechanism. Noninvasively, this arrhythmogenic substrate was approached using multilead body surface potential mapping, but also QT interval dispersion (QTd) and similar electrocardiogram (ECG) variables from the 12-lead surface ECG. Standard QTd from the ECG correlates significantly with dispersion of repolarization measured from the myocardium. A causal relationship is, however, still unclear, and there are 2 main hypotheses to explain the electrophysiological basis of QTd. The local hypothesis explaining QTd with spatial differences in action potential duration mirrored in the various QT intervals competes with the global hypothesis explaining the variation in surface ECG measurements with different projections of a common T-wave vector. Notwithstanding the final explanation for QTd, and particularly for technical reasons, new markers like advanced T-wave loop variables may best reflect the abnormal repolarization substrate on the surface ECG.

High dispersion of ventricular repolarization after an implantable defibrillator shock predicts induction of ventricular fibrillation as well as unsuccessful defibrillation.

OBJECTIVES: To test the hypothesis that post-shock dispersion of repolarization (PSDR) is higher in T wave shocks that induce ventricular fibrillation (VF) than in those that do not, as well as in implantable cardioverter defibrillator (ICD) defibrillation shocks which fail to terminate VF when compared with those that are successful. BACKGROUND: Ventricular fibrillation has been linked to the presence of dispersion of repolarization, which facilitates reentry. Most of the studies have been done in animals, and the mechanism underlying the generation and termination of VF in humans is speculative and remains to be determined. METHODS: Monophasic action potentials (MAPs) were recorded simultaneously from the right ventricular outflow tract (RVOT) and the right ventricular apex (RVA) in 27 patients who underwent implantation and testing of an ICD. T wave shocks were used to induce VF while the termination was attempted using internal defibrillator shocks. The post-shock repolarization time (PSRT) was measured in both the RVA and RVOT MAPs, and the difference between the two recordings was defined as the PSDR. The averages of PSDR were compared between the successful and unsuccessful inductions and terminations of VF. RESULTS: T wave shocks that induced VF generated a greater PSDR (93.4 +/- 85.1 ms) than the unsuccessful ones (45.1 +/- 55.9 ms, p < 0.001). On the other hand, shocks that failed to terminate VF were associated with a greater PSDR (59.9 +/- 41.2 ms) than shocks that terminated VF (21.1 +/- 20.1 ms), p < 0.001. CONCLUSIONS: A high PSDR following a T wave shock is associated with induction of VF; while following a defibrillating shock, it is associated with its failure and the continuation of VF. Conversely, a low PSDR is associated with failure of a T wave shock to induce VF and successful termination of VF by a defibrillating shock.

[Mechanism of induction and termination of ventricular fibrillation--significance of dispersion of ventricular repolarization]. / Mechanismus der Induktion und Terminierung von Kammerflimmern--Bedeutung der Dispersion der ventrikulären Repolarisation.

It has been known for many years that ventricular fibrillation may be induced and terminated by electrical field stimuli. Recent experimental studies have shown that both fibrillation and defibrillation have a common electrophysiologic mechanism that is based on the interaction between the electrical field stimulus and ventricular repolarization. Ventricular fibrillation will be induced if the field stimulus is applied with the area of vulnerability, this area of vulnerability is defined two dimensionally by the shock coupling interval and shock strength, and is modified by the configuration of the shock. A field shock that is applied within the area of vulnerability causes heterogeneity of ventricular repolarization immediately after the shock (postshock dispersion), thereby enabling the development of circuit movements and reentry, and resulting in ventricular fibrillation. High energy shocks, however, that are applied above the area of vulnerability (i.e., above the upper limit of vulnerability) will not induce ventricular fibrillation due to homogeneous prolongation of repolarization and a resulting small postshock dispersion. In analogy, ventricular fibrillation will continue after unsuccessful low-energy defibrillation shocks due to high postshock dispersion, whereas a high-energy shock will synchronize ventricular repolarization, thereby causing small postshock dispersion and termination of ventricular fibrillation. This paper describes the relation between fibrillation, defibrillation and ventricular repolarization based on experimental findings. A possible clinical application of these findings is that the upper limit of vulnerability may be used as a surrogate for the defibrillation threshold. Thus, defibrillation threshold testing may not be necessary during future implantations of automatic cardioverter defibrillators.

Female gender is a risk factor for torsades de pointes in an in vitro animal model.

Recent clinical observations indicate that female gender is associated with a higher risk of developing torsades de pointes (TdP) cardiac arrhythmia. In this study, we used the Langendorff technique in isolated perfused rabbit hearts and the whole-cell patch-clamp technique in ventricular myocytes to examine the gender difference in TdP incidence and gain insight into the underlying mechanisms. Isolated rabbit hearts were perfused by using the Langendorff technique. TdP was induced by abrupt changes of cycle length (deltaCL) in the presence of Tyrode's solution containing 1 mM 4-aminopyridine (4AP) and 50% reduced Mg2+ and K+ (low K/Mg). The effects of 1 mM 4AP on cardiac potassium currents were characterized by using the patch-clamp technique. Results demonstrated that (a) no significant gender difference was observed in the absolute QT interval before or after 4AP perfusion in the presence of low K/Mg; (b) 4AP caused marked QT prolongation in the ECG; (c) a significantly higher TdP incidence (nine of 12) was found in female hearts compared with male hearts (three of 12; p < 0.05); (d) 1 mM 4AP primarily inhibited Ito, although a slight inhibition of IKr also occurred in low-K/Mg Tyrode's solution. (e) No inhibition of IK1 was observed. (f) No gender difference was found in the potassium current block produced by 4AP. Female gender is associated with a higher incidence of TdP in an experimental isolated heart model and mechanisms subsequent to QT prolongation may contribute to such a gender difference.

Phase angle convergence of multiple monophasic action potential recordings precedes spontaneous termination of ventricular fibrillation.

AIMS: To elucidate the mechanism of spontaneous termination of ventricular fibrillation (VF) and to define an indicator of its occurrence, the phase angle, a novel measure to assess synchrony of activation, was evaluated. METHODS AND RESULTS: In 7 isolated rabbit hearts, 7 monophasic action potentials were recorded simultaneously. Ventricular fibrillation was induced by T wave shocks. Cycle lengths (CL) and phase angles between all 7 recordings were analyzed until spontaneous termination or shock-induced defibrillation. Average phase angle was calculated as activation time difference to a reference channel and expressed as a fraction of the reference channel's CL with 1 equaling a complete CL. Initial CLs and phase angles were similar in sustained and terminating episodes (CL: 141 +/- 16 ms vs 142 +/- 24 ms, phase angle: 0.244 +/- 0.11 vs 0.263 +/- 0.1, p = NS). During spontaneous termination, CL increased slightly by 7%. Average phase angle converged gradually over the last three activations before termination of ventricular fibrillation by 22-48% (p < 0.0005), eventually resulting in phase angles similar to paced rhythms directly prior to spontaneous termination of ventricular fibrillation. CONCLUSIONS: Gradual synchronization of activation is part of the electrophysiological mechanism resulting in spontaneous ventricular fibrillation termination and can be detected three activations before termination. Phase angle convergence may be useful to detect spontaneous termination of ventricular fibrillation.