HYSTERESIS IN REPOLARIZATION OF CARDIAC ACTION POTENTIALS: EFFECTS OF SPATIAL HETEROGENEITY AND SLOW REPOLARIZATION CURRENTS

Repolarization alternans, i.e. beat-to-beat variation of repolarization of action potential, is proposed as a predictor of life-threatening arrhythmias. Restitution relates repolarization duration with its previous relaxation time, i.e. diatstolic interval (DI), and is considered a dominant mechanism for alternans. Previously, we observed that different repolarization durations at the same DI during decelerating and accelerating pacing, i.e. restitution displays hysteresis, which is a measure of “cardiac memory”. Objective of the current study was to investigate in the pig 1) the mechanism for a previously observed hysteresis type phenomenon, where alternans, once started at higher heart rate, persists even when heart rate decreases below its initiating rate, 2) regional differences in expression of hysteresis, i.e. memory in restitution in the heart, and 3) changes in restitution and memory during manipulation of an important repolarization current, the slow delayed rectifier, IKs. Action potentials were recorded in pig ventricular tissues using microelectrodes. Regional differences were explored in endocardial and epicardial tissues from both ventricles. DIs were explicitly controlled in real time to separate restitution mechanism from non-restitution related effects. Stepwise protocols were used to explore the existence in hysteresis in alternans threshold, where DIs were held constant for each step and progressively decreased and then increased. Quantification of cardiac memory was achieved by sinusoidally changing DI protocols, which were used to investigate memory changes among myocytes from different regions of the heart and during IKs manipulation. Results show that during stepwise protocol, hysteresis in alternans still existed, which indicates that restitution is not the only mechanism underlying the hysteresis. When comparing hysteresis obtained from sinusoidally oscillatory DIs among different regions, results show memory is expressed differently with endocardium expressing the most and epicardium the least memory. This provides important implications about the location where arrhythmia would initiate. Results also show that measures for hysteresis loops obtained by sinusoidal DI protocols decreased (increased) after enhancement (attenuation) of IKs, suggesting decreased (increased) hysteresis, i.e. memory in restitution. This effect needs to be considered during drug development

Supernormal Conduction and Suppression of Spatially Discordant Alternans of Cardiac Action Potentials

Spatially discordant alternans (DA) of action potential durations (APD) is thought to be more pro-arrhythmic than concordant alternans. Super normal conduction (SNC) has been reported to suppress formation of DA. An increase in conduction velocity (CV) as activation rate increases, i.e., a negative CV restitution, is widely considered as hallmark of SNC. Our aim in this study is to show that it is not an increase in CV for faster rates that prevents formation of DA, rather, it is the ratio of the CV for the short relative to the long activation that is critical in DA suppression. To illustrate this subtlety, we simulated this phenomenon using two approaches; (1) by using the standard, i.e., S1S2 protocol to quantify restitution and disabling the slow inactivation gate j of the sodium current (INa), and (2) by using the dynamic, i.e., S1S1 protocol for quantification of restitution and increasing INa at different cycle lengths (CL). Even though both approaches produced similar CV restitution curves, DA was suppressed only during the first approach, where the CV of the short of the long-short action potential (AP) pattern was selectively increased. These results show that negative CV restitution, which is considered characteristic of SNC, per se, is not causal in suppressing DA, rather, the critical factor is a change in the ratio of the velocities of the short and the long APs

Supernormal Conduction and Suppression of Spatially Discordant Alternans of Cardiac Action Potentials

Spatially discordant alternans (DA) of action potential durations (APD) is thought to be more pro-arrhythmic than concordant alternans. Super normal conduction (SNC) has been reported to suppress formation of DA. An increase in conduction velocity (CV) as activation rate increases, i.e., a negative CV restitution, is widely considered as hallmark of SNC. Our aim in this study is to show that it is not an increase in CV for faster rates that prevents formation of DA, rather, it is the ratio of the CV for the short relative to the long activation that is critical in DA suppression. To illustrate this subtlety, we simulated this phenomenon using two approaches; (1) by using the standard, i.e., S1S2 protocol to quantify restitution and disabling the slow inactivation gate j of the sodium current (INa), and (2) by using the dynamic, i.e., S1S1 protocol for quantification of restitution and increasing INa at different cycle lengths (CL). Even though both approaches produced similar CV restitution curves, DA was suppressed only during the first approach, where the CV of the short of the long-short action potential (AP) pattern was selectively increased. These results show that negative CV restitution, which is considered characteristic of SNC, per se, is not causal in suppressing DA, rather, the critical factor is a change in the ratio of the velocities of the short and the long APs

Research Directions and Projects In an Institute of Developmental Psychology in China

We are a team who maintained to focus on 3 fields in people’s mental health recent years: marriage and family research and therapy, mental health of middle and primary school students, and internet addiction in youth. In every field, we focus on both fundamental research and clinical practice. We aim to explore mechanisms using survey, observation and cognitive neuroscience methods (fMRI), and develop prediction and intervention projects based on research, to improve people’s life and policies

Phase Relationship between Alternans of Early and Late Phases of Ventricular Action Potentials

Background: Alternans of early phase and of duration of action potential (AP) critically affect dispersion of refractoriness through their influence on conduction and repolarization. We investigated the phase relationship between the two alternans and its effect on conduction. Methods and Results: Transmembrane potentials recorded from ventricles of eight swine and three canines during paced activation intervals of ≤300 ms were used to quantify alternans of maximum rate of depolarization (|dv/dt|max) and of action potential duration (APD). Incidence of APD alternans was 62 and 76% in swine and canines. Alternans of APD was frequently accompanied with alternans of |dv/dt|max. Of these, 4 and 26% were out of phase in swine and canines, i.e., low |dv/dt|max preceded long APD. Computer simulations show that out of phase alternans attenuate variation of wavelength and thus minimize formation of spatially discordant alternans. Conclusion: The spontaneous switching of phase relationship between alternans of depolarization and repolarization suggests that mechanisms underlying these alternans may operate independent of each other. The phase between these alternans can critically impact spatial dispersion of refractoriness and thus stability of conduction, with the in phase relation promoting transition from concord to discord while out of phase preventing formation of discord

Comparison of Left Ventricular Strains and Torsion Derived from Feature Tracking and DENSE CMR

Background: Cardiovascular magnetic resonance (CMR) feature tracking is increasingly used to quantify cardiac mechanics from cine CMR imaging, although validation against reference standard techniques has been limited. Furthermore, studies have suggested that commonly-derived metrics, such as peak global strain (reported in 63% of feature tracking studies), can be quantified using contours from just two frames – end-diastole (ED) and end-systole (ES) – without requiring tracking software. We hypothesized that mechanics derived from feature tracking would not agree with those derived from a reference standard (displacement-encoding with stimulated echoes (DENSE) imaging), and that peak strain from feature tracking would agree with that derived using simple processing of only ED and ES contours. Methods: We retrospectively identified 88 participants with 186 pairs of DENSE and balanced steady state free precession (bSSFP) image slices acquired at the same locations across two institutions. Left ventricular (LV) strains, torsion, and dyssynchrony were quantified from both feature tracking (TomTec Imaging Systems, Circle Cardiovascular Imaging) and DENSE. Contour-based strains from bSSFP images were derived from ED and ES contours. Agreement was assessed with Bland-Altman analyses and coefficients of variation (CoV). All biases are reported in absolute percentage. Results: Comparison results were similar for both vendor packages (TomTec and Circle), and thus only TomTec Imaging System data are reported in the abstract for simplicity. Compared to DENSE, mid-ventricular circumferential strain (Ecc) from feature tracking had acceptable agreement (bias: − 0.4%, p = 0.36, CoV: 11%). However, feature tracking significantly overestimated the magnitude of Ecc at the base (bias: − 4.0% absolute, p \u3c 0.001, CoV: 18%) and apex (bias: − 2.4% absolute, p = 0.01, CoV: 15%), underestimated torsion (bias: − 1.4 deg/cm, p \u3c 0.001, CoV: 41%), and overestimated dyssynchrony (bias: 26 ms, p \u3c 0.001, CoV: 76%). Longitudinal strain (Ell) had borderline-acceptable agreement (bias: − 0.2%, p = 0.77, CoV: 19%). Contour-based strains had excellent agreement with feature tracking (biases: − 1.3–0.2%, CoVs: 3–7%). Conclusion: Compared to DENSE as a reference standard, feature tracking was inaccurate for quantification of apical and basal LV circumferential strains, longitudinal strain, torsion, and dyssynchrony. Feature tracking was only accurate for quantification of mid LV circumferential strain. Moreover, feature tracking is unnecessary for quantification of whole-slice strains (e.g. base, apex), since simplified processing of only ED and ES contours yields very similar results to those derived from feature tracking. Current feature tracking technology therefore has limited utility for quantification of cardiac mechanics

Assessment of intra- and inter-ventricular cardiac dyssynchrony in patients with repaired Tetralogy of Fallot: a cardiac magnetic resonance study

Using radiative magnetohydrodynamic simulations of the magnetized solar photosphere and detailed spectro-polarimetric diagnostics with the Fe I 6301.5 Å and 6302.5 Å photospheric lines in the local thermodynamic equilibrium approximation, we model active solar granulation as if it was observed at the solar limb. We analyze general properties of the radiation across the solar limb, such as the continuum and the line core limb darkening and the granulation contrast. We demonstrate the presence of profiles with both emission and absorption features at the simulated solar limb, and pure emission profiles above the limb. These profiles are associated with the regions of strong linear polarization of the emergent radiation, indicating the influence of the intergranular magnetic fields on the line formation. We analyze physical origins of the emission wings in the Stokes profiles at the limb, and demonstrate that these features are produced by localized heating and torsional motions in the intergranular magnetic flux concentrations

High Resolution Cine Displacement Encoding with Stimulated Echoes (DENSE) at 3T with Navigator Feedback for Quantification of Cardiac Mechanics

Background: Measures of cardiac mechanics such as myocardial wall strain are better predictors of outcomes in patients with heart disease compared to traditional clinical measures and ejection fraction. Cine displacement encoding with stimulated echoes (DENSE) is an ideal method for quantifying cardiac motion which encodes tissue displacement in the phase of the MR signal and provides pixel-level resolution for quantifying cardiac mechanics. To date, DENSE has been implemented with resolution limited to 2-3 pixels across the myocardium. While this resolution is higher than most other techniques for quantifying cardiac mechanics, it may limit the ability of DENSE to quantify finer details such as transmural strains (subendocardial, midmyocardial and subepicardial) and right ventricular mechanics. We hypothesized that it is possible to efficiently increase the resolution of DENSE by a factor of 4 utilizing a navigator feedback system. Methods: 10 subjects (age 27 ± 3) with normal ECG and no history of cardiovascular disease were consented. A 3.0T Siemens Tim Trio with a 6-element chest and 24-element spine coil was configured with a navigator feedback system. The feedback system projected the navigator image of the diaphragm to the subject in real time to optimize breathold position. Standard resolution 2D cine DENSE was acquired with: 6 spiral interleaves, FOV = 340 mm, matrix = 96 × 96, thickness = 8 mm, TE/TR = 1.08/17, flip angle = 20, averages = 1, navigator acceptance window = ± 3 mm. High resolution 2D cine DENSE images were acquired by quadrupling the number of spirals to 24, increasing the matrix to 256 × 256, and increasing the averages to 3. Three short- and two long-axis images were acquired with each technique. Left ventricular strains and torsion were compared between the techniques using Bland-Altman. Results: The high resolution images took 11 times longer to acquire but the navigator feedback system provided good efficiency (69 ± 9%) for a total acquisition time of roughly 5 minutes per slice. The high resolution images had excellent quality with a noticeable improvement over standard resolution. There was a systematic but negligible difference between standard and high resolution data for circumferential and longitudinal strains. Radial strains showed the largest differences consistent with a systematic under-estimation of radial strain from standard resolution DENSE. Torsion was not significantly different between the two methods. Conclusions: High resolution cine DENSE MRI with navigator feedback is feasible at 3T and produces high quality images with 4 times the resolution of standard DENSE. Left ventricular circumferential strains, longitudinal strains, and torsion showed negligible differences between high and low resolution DENSE. Radial strains were significantly different, potentially due to better accuracy with high resolution DENSE due to the increased number of pixels within the thickness of the myocardial wall