Yuanna Cheng

Virtual Electrode–Induced Phase Singularity: A Basic Mechanism of Defibrillation Failure

Delivery of a strong electric shock to the heart remains the only effective therapy against ventricular fibrillation. Despite significant improvements in implantable cardioverter defibrillator (ICD) therapy, the fundamental mechanisms of defibrillation remain poorly understood. We have recently demonstrated that a monophasic defibrillation shock produces a highly nonuniform epicardial polarization pattern, referred to as a virtual electrode pattern (VEP). The VEP consists of large adjacent areas of strong positive and negative polarization. We sought to determine whether the VEP may be responsible for defibrillation failure by creating dispersion of postshock repolarization and reentry. Truncated exponential biphasic and monophasic shocks were delivered from a bipolar ICD lead in Langendorff-perfused rabbit hearts. Epicardial electrical activity was mapped during and after defibrillation shocks and shocks applied at the plateau phase of a normal action potential produced by ventricular pacing. A high-resolution fluorescence mapping system with 256 recording sites and a voltage-sensitive dye were used. Biphasic shocks with a weak second phase (<20% leading-edge voltage of the second phase with respect to the leading-edge voltage of the first phase) produced VEPs similar to monophasic shocks. Biphasic shocks with a strong second phase (>70%) produced VEPs of reversed polarity. Both of these waveforms resulted in extra beats and arrhythmias. However, biphasic waveforms with intermediate second-phase voltages (20% to 70% of first-phase voltage) produced no VEP, because of an asymmetric reversal of the first-phase polarization. Therefore, there was no substrate for postshock dispersion of repolarization. Shocks producing strong VEPs resulted in postshock reentrant arrhythmias via a mechanism of phase singularity. Points of phase singularity were created by the shock in the intersection of areas of positive, negative, and no polarization, which were set by the shock to excited, excitable, and refractory states, respectively. Shock-induced VEPs may reinduce arrhythmias via a phase-singularity mechanism. Strong shocks may overcome the preshock electrical activity and create phase singularities, regardless of the preshock phase distribution. Optimal defibrillation waveforms did not produce VEPs because of an asymmetric effect of phase reversal on membrane polarization.

Virtual Electrode–Induced Reexcitation A Mechanism of Defibrillation

Mechanisms of defibrillation remain poorly understood. Defibrillation success depends on the elimination of fibrillation without shock-induced arrhythmogenesis. We optically mapped selected epicardial regions of rabbit hearts (n=20) during shocks applied with the use of implantable defibrillator electrodes during the refractory period. Monophasic shocks resulted in virtual electrode polarization (VEP). Positive values of VEP resulted in a prolongation of the action potential duration, whereas negative polarization shortened the action potential duration, resulting in partial or complete recovery of the excitability. After a shock, new propagated wavefronts emerged at the boundary between the 2 regions and reexcited negatively polarized regions. Conduction velocity and maximum action potential upstroke rate of rise dV/dt (max) of shock-induced activation depended on the transmembrane potential at the end of the shock. Linear regression analysis showed that dV/dt(max) of postshock activation reached 50% of that of normal action potential at a V(m) value of -56.7+/-0.6 mV postshock voltage (n=9257). Less negative potentials resulted in slow conduction and blocks, whereas more negative potentials resulted in faster conduction. Although wavebreaks were produced in either condition, they degenerated into arrhythmias only when conduction was slow. Shock-induced VEP is essential in extinguishing fibrillation but can reinduce arrhythmias by producing excitable gaps. Reexcitation of these gaps through progressive increase in shock strength may provide the basis for the lower and upper limits of vulnerability. The former may correspond to the origination of slow wavefronts of reexcitation and phase singularities. The latter corresponds to fast conduction during which wavebreaks no longer produce sustained arrhythmias.

Evidence of Three‐Dimensional Scroll Waves with Ribbon‐Shaped Filament as a Mechanism of Ventricular Tachycardia in the Isolated Rabbit Heart

Scroll Waves in the Heart. Introduction: Rotating vortices have been observed in excitable media of different nature. Vortices may sustain life or kill in different species, by underlining morphogenesis in Dictiostelium discoideum during starvation, or arrhythmias during sudden cardiac death in mammals. Investigation of vortices in the heart has been limited by two‐dimensional experimental techniques. In contrast, three‐dimensional (3D) Belousov‐Zhabotinsky excitable medium and mathematical models have been shown to sustain scroll‐shaped waves. The heart is a 3D structure; therefore, scroll waves may underlie cardiac arrhythmias.

Direct Evidence of the Role of Virtual Electrode-Induced Phase Singularity in Success and Failure of Defibrillation

Virtual Electrodes in Defibrillation. Introduction: We recently demonstrated that virtual electrode‐induced phase singularity is responsible for arrhythmogenesis during T wave shocks and explains the upper and lower limits of vulnerability. Furthermore, we suggested that the same mechanism might he responsible for defibrillation failure. The aim of this study was to experimentally support this hypothesis.

High‐Resolution Fluorescent Imaging Does Not Reveal a Distinct Atrioventricular Nodal Anterior Input Channel (Fast Pathway) in the Rabbit Heart During Sinus Rhythm

Fluorescent Imaging of AVN. Introduction: We sought to determine the precise pathways of engagement of the AV node during sinus rhythm.

Differences in left ventricular long‐axis function from mice to humans follow allometric scaling to ventricular size

While the heart size maintains a constant proportion to body size, heart function parameters, such as heart rate and cardiac output, show a more complex scaling pattern. How these phenomena affect the long‐axis left ventricular (LV) function is unknown. We studied 10 mice, 15 rats, 6 rabbits, 8 mongrel dogs and 38 human volunteers. Doppler tissue echocardiography data were postprocessed to reconstruct mitral annulus (MA) peak systolic velocity and displacement. The relationship between MA peak velocity, MA displacement and LV ejection time, and LV end‐diastolic volume (and mass) were fit to an allometric (power‐law) equation Y=kMβ. LV mass varied from 0.062 to 255 g, while end‐diastolic volume varied from 0.014 to 205 ml. β values of the relation between LV ejection time and LV end‐diastolic volume and mass were 0.247 ± 0.017 and 0.267 ± 0.018, respectively. β values of the relationship between MA displacement and LV end‐diastolic volume and mass were 0.358 ± 0.047 and 0.390 ± 0.051 (P < 0.023 versusβ of LV ejection time). β values of the relationship between MA peak systolic velocity and LV end‐diastolic volume and mass were 0.096 ± 0.012 and 0.100 ± 0.013, respectively (P < 0.0001 versus 0). Finally, β values of the relationship between the long‐to‐short axis displacement ratio and LV end‐diastolic volume and mass were 0.077 ± 0.017 and 0.086 ± 0.019 (P < 0.0001 versus 0). We conclude that MA velocity, displacement, and long‐to‐short axis displacement ratio scale allometrically to heart size. This reduces the relative long‐axis contribution to heart function in small mammals.

Reversal of Repolarization Gradient Does Not Reverse the Chirality of Shock-Induced Reentry in the Rabbit Heart

Chirality and Repolarization. Introduction: Two hypotheses have been proposed to explain the mechanisms of vulnerability and related failure of defibrillation therapy: the cross‐field‐induced critical point hypothesis and the virtual electrode‐induced phase singularity hypothesis. These two hypotheses predict the opposite effect of preshock repolarization on the chirality (direction of rotation) of shock‐induced reentry. The former suggests its reversal upon reversal of repolarization, whereas the latter suggests its preservation. The aim of this study was to determine, by reversing the repolarization sequence, which of the mechanisms is responsible for internal shock‐induced arrhythmia in the Langendorff‐perfused rabbit heart.

How similar are the mice to men? Between-species comparison of left ventricular mechanics using strain imaging

Background While mammalian heart size maintains constant proportion to whole body size, scaling of left ventricular (LV) function parameters shows a more complex scaling pattern. We used 2-D speckle tracking strain imaging to determine whether LV myocardial strains and strain rates scale to heart size. Methods We studied 18 mice, 15 rats, 6 rabbits, 12 dogs and 20 human volunteers by 2-D echocardiography. Relationship between longitudinal or circumferential strains/strain rates (SLong/SRLong, SCirc/SRCirc), and LV end-diastolic volume (EDV) or mass were assessed by the allometric (power-law) equation Y = kMβ. Results Mean LV mass in individual species varied from 0.038 to 134 g, LV EDV varied from 0.015 to 102 ml, while RR interval varied from 81 to 1090 ms. While SLong increased with increasing LV EDV or mass (β values 0.047±0.006 and 0.051±0.005, p<0.0001 vs. 0 for both) SCirc was unchanged (p = NS for both LV EDV or mass). Systolic and diastolic SRLong and SRCirc showed inverse correlations to LV EDV or mass (p<0.0001 vs. 0 for all comparisons). The ratio between SLong and SCirc increased with increasing values of LV EDV or mass (β values 0.039±0.010 and 0.040±0.011, p>0.0003 for both). Conclusions While SCirc is unchanged, SLong increases with increasing heart size, indicating that large mammals rely more on long axis contribution to systolic function. SRLong and SRCirc, both diastolic and systolic, show an expected decrease with increasing heart size.

Membrane Time Constant During Internal Defibrillation Strength Shocks in Intact Heart: Effects of Na+ and Ca2+ Channel Blockers

Introduction: We assessed defibrillation strength shock‐induced changes of the membrane time constant (τ) and membrane potential (ΔVm) in intact rabbit hearts after administration of lidocaine, a sodium (Na+) channel blocker, or nifedipine, a L‐type calcium (Ca2+) channel blocker.

Electroporation induced by internal defibrillation shock with and without recovery in intact rabbit hearts

Defibrillation shocks from implantable cardioverter defibrillators can be lifesaving but can also damage cardiac tissues via electroporation. This study characterizes the spatial distribution and extent of defibrillation shock-induced electroporation with and without a 45-min postshock period for cell membranes to recover. Langendorff-perfused rabbit hearts (n = 31) with and without a chronic left ventricular (LV) myocardial infarction (MI) were studied. Mean defibrillation threshold (DFT) was determined to be 161.4 ± 17.1 V and 1.65 ± 0.44 J in MI hearts for internally delivered 8-ms monophasic truncated exponential (MTE) shocks during sustained ventricular fibrillation (>20 s, SVF). A single 300-V MTE shock (twice determined DFT voltage) was used to terminate SVF. Shock-induced electroporation was assessed by propidium iodide (PI) uptake. Ventricular PI staining was quantified by fluorescent imaging. Histological analysis was performed using Massons Trichrome staining. Results showed PI staining concentrated near the shock electrode in all hearts. Without recovery, PI staining was similar between normal and MI groups around the shock electrode and over the whole ventricles. However, MI hearts had greater total PI uptake in anterior (P < 0.01) and posterior (P < 0.01) LV epicardial regions. Postrecovery, PI staining was reduced substantially, but residual staining remained significant with similar spacial distributions. PI staining under SVF was similar to previously studied paced hearts. In conclusion, electroporation was spatially correlated with the active region of the shock electrode. Additional electroporation occurred in the LV epicardium of MI hearts, in the infarct border zone. Recovery of membrane integrity postelectroporation is likely a prolonged process. Short periods of SVF did not affect electroporation injury.