Excitation and Injury of Adult Ventricular Cardiomyocytes by Nano- to Millisecond Electric Shocks

Intense electric shocks of nanosecond (ns) duration can become a new modality for more efficient but safer defibrillation. We extended strength-duration curves for excitation of cardiomyocytes down to 200 ns, and compared electroporative damage by proportionally more intense shocks of different duration. Enzymatically isolated murine, rabbit, and swine adult ventricular cardiomyocytes (VCM) were loaded with a Ca2+ indicator Fluo-4 or Fluo-5N and subjected to shocks of increasing amplitude until a Ca2+ transient was optically detected. Then, the voltage was increased 5-fold, and the electric cell injury was quantified by the uptake of a membrane permeability marker dye, propidium iodide. We established that: (1) Stimuli down to 200-ns duration can elicit Ca2+ transients, although repeated ns shocks often evoke abnormal responses, (2) Stimulation thresholds expectedly increase as the shock duration decreases, similarly for VCMs from different species, (3) Stimulation threshold energy is minimal for the shortest shocks, (4) VCM orientation with respect to the electric field does not affect the threshold for ns shocks, and (5) The shortest shocks cause the least electroporation injury. These findings support further exploration of ns defibrillation, although abnormal response patterns to repetitive ns stimuli are of a concern and require mechanistic analysis

Nanosecond Stimulation and Defibrillation of Langendorff-Perfused Rabbit Hearts

The search for novel defibrillation methodologies focuses on minimizing deposition of energy to the heart, as this is an indicator for side effects including pain and tissue death. In this work, we investigate the effect of reducing the duration of the applied shocks from low milliseconds to the nanosecond range. 300 ns defibrillation was observed and confirmed to require lower energy than monophasic shocks by almost an order of magnitude with no tissue damage. Additionally, the safety factor, the ratio of median effective doses for electroporative damage and defibrillation, was similar for both durations. To predict how defibrillation shocks of any duration affect the heart, the stimulation strength-duration curve from 200 ns to 10 ms was determined. To investigate whether high frequency trains of nanosecond shocks (MHz compression) are capable of reducing the electric field and energy of defibrillation, they were compared with a single shock of the same duration. The average voltage for the pulse trains was slightly lower than for long shocks, but the energy almost doubled. Finally, to understand how shocks even shorter than 300 ns perform, we attempted to determine the defibrillation threshold of 60 ns shocks. Both the estimated electric field and energy were markedly higher than for 300 ns. We also investigated the stimulation threshold of 60 ns shocks followed by a negative phase of varying amplitude and showed that the negative phase reduces the ability of the shocks to stimulate. In conclusion, this work contributes to the understanding of how nanosecond shocks interact with cardiac tissues. It shows that 300 ns defibrillation is effective and similarly safe as 10 ms shocks, while requiring almost an order of magnitude less energy. The stimulation strength duration curve for cardiac tissue follows the same trend, with lower than expected thresholds for nanosecond shocks. However, low voltage MHz compressed nanosecond shocks are similarly effective as long shocks of the same duration, indicating that the greater efficacy of nanosecond defibrillation is linked to the effects of high voltage. Finally, investigations in 60 ns shocks show defibrillation and stimulation are possible, and that bipolar cancellation occurs in cardiac tissue

Advantage of four-electrode over two-electrode defibrillators

Defibrillation is the standard clinical treatment used to stop ventricular fibrillation. An electrical device delivers a controlled amount of electrical energy via a pair of electrodes in order to reestablish the normal heart rate. We propose a new technique that is a combination of biphasic shocks applied with a four-electrode system rather than the standard two-electrode system. We use a numerical model of a one-dimensional ring of cardiac tissue in order to test and evaluate the benefit of such a new technique. We compare three different shock protocols, namely, a monophasic and two types of biphasic shocks. The results obtained by using a four-electrode system are compared quantitatively with those obtained with the standard two-electrode system. We find that a huge reduction in defibrillation threshold is achieved with the four-electrode system. For the most efficient protocol (asymmetric biphasic), we obtain a reduction in excess of 80 % in the energy required for a defibrillation success rate of 90 %. The mechanisms of successful defibrillation are also analyzed. This reveals that the advantage of asymmetric biphasic shocks with four electrodes lies in the duration of the cathodal and anodal phase of the shock

Analysis of current density and related parameters in spinal cord stimulation

A volume conductor model of the spinal cord and surrounding anatomical structures is used to calculate current (and current density) charge per pulse, and maximum charge density per pulse at the contact surface of the electrode in the dorsal epidural space, in the dorsal columns of the spinal cord and in the dorsal roots. The effects of various contact configurations (mono-, bi-, and tripole), contact area and spacing, pulsewidth and distance between contacts and spinal cord on these electrical parameters were investigated under conditions similar to those in clinical spinal cord stimulation. At the threshold stimulus of a large dorsal column fiber, current density and charge density per pulse at the contact surface were found to be highest (1.9·105 ¿A/cm2 and 39.1 ¿C/cm2 ·p, respectively) when the contact surface was only 0.7 mm 2. When stimulating with a pulse of 500 ¿s, highest charge per pulse (0.92 ¿C/p), and the largest charge density per pulse in the dorsal columns (1.59 ¿C/cm2·p) occurred. It is concluded that of all stimulation parameters that can be selected freely, only pulsewidth affects the charge and charge density per pulse in the nervous tissue, whereas both pulsewidth and contact area strongly affect these parameters in the nonnervous tissue neighboring the electrode contact

Electroporation safety factor of 300 nanosecond and 10 millisecond defibrillation in Langendorff-perfused rabbit hearts

AIMS: Recently, a new defibrillation modality using nanosecond pulses was shown to be effective at much lower energies than conventional 10 millisecond monophasic shocks in ex vivo experiments. Here we compare the safety factors of 300 nanosecond and 10 millisecond shocks to assess the safety of nanosecond defibrillation. METHODS AND RESULTS: The safety factor, i.e. the ratio of median effective doses (ED50) for electroporative damage and defibrillation, was assessed for nanosecond and conventional (millisecond) defibrillation shocks in Langendorff-perfused New Zealand white rabbit hearts. In order to allow for multiple shock applications in a single heart, a pair of needle electrodes was used to apply shocks of varying voltage. Propidium iodide (PI) staining at the surface of the heart showed that nanosecond shocks had a slightly lower safety factor (6.50) than millisecond shocks (8.69), p = 0.02; while PI staining cross-sections in the electrode plane showed no significant difference (5.38 for 300 ns shocks and 6.29 for 10 ms shocks, p = 0.22). CONCLUSIONS: In Langendorff-perfused rabbit hearts, nanosecond defibrillation has a similar safety factor as millisecond defibrillation, between 5 and 9, suggesting that nanosecond defibrillation can be performed safely

Effect of Electrode Placement on Defibrillation Threshold and Esophageal Electric Field in Internal Atrial Defibrillation

Atrial fibrillation is the most common heart arrhythmia of clinical significance. Internal cardioversion can be used to restore sinus rhythm; however, the amount of delivered energy elicits intolerable pain. Lowering delivered energy could make implantable cardioverters a promising treatment option. This study simulated cardioversion shocks in a model of the human heart using finite element analysis to determine effects of different electrode placements on defibrillation threshold (DFT) and esophageal electric field (EEF) near the left atrium. Ten right atrial to coronary sinus electrode placements were tested. Small shifts in electrode placements changed DFT by up to 42%, indicating electrode position is an important factor in lowering DFT. A relationship was not discovered between EEF and DFT. If a relationship can be discovered between an alternate EEF or other measure and DFT, electrode placements could be optimized on a patient-specific basis to lower delivered energy to painless or tolerable levels