Heart defibrillation: relationship between pacing threshold and defibrillation probability
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Considering the clinical importance of the ventricular fibrillation and that the most used therapy to reverse it has a critical side effect on the cardiac tissue, it is desirable to optimize defibrillation parameters to increase its efficiency. In this study, we investigated the influence of stimuli duration on the relationship between pacing threshold and defibrillation probability.
We found out that 0.5-ms-long pulses had a lower ratio of defibrillation probability to the pacing threshold, although the higher the pulse duration the lower is the electric field intensity required to defibrillate the hearts.
The appropriate choice of defibrillatory shock parameters is able to increase the efficiency of the defibrillation improving the survival chances after the occurrence of a severe arrhythmia. The relationship between pulse duration and the probability of reversal of fibrillation shows that this parameter cannot be underestimated in defibrillator design since different pulse durations have different levels of safety.
KeywordsVentricular fibrillation Defibrillation Electric stimulation Isolated rat heart preparation
transmembrane potential variation
transmembrane potential variation threshold
automated external defibrillators
high-intensity electric field
the average value of HEF corresponding to 50% of defibrillation probability
high-intensity electric field necessary to successful defibrillation
high-intensity electrical stimulator
low-intensity electrical stimulator
out-of-hospital cardiac arrest
standard error of the mean
video signal edge detector
Life-threatening arrhythmias (LTA) such as ventricular fibrillation (VF) are very serious conditions that may lead to death in few minutes. VF is characterized by chaotic and asynchronous cardiomyocyte electrical activity which leads to ineffective heart pumping . It has a prevalence of approximately ~ 25–50% of people with out-of-hospital cardiac arrest (OHCA) [2, 3, 4]. LTA are one of the major causes of death around the world. Annually, 35 per 100,000 people experience OHCA globally, including adults and children, and this number increases to 62 per 100,000 people when only adults are taken in account .
Once LTA are diagnosed, a high-intensity electric field (HEF) must be applied in the patient as soon as a defibrillator is available in a procedure called defibrillation . For effective defibrillation, a critical mass (75–90%) of ventricular cardiomyocytes has to be excited at the same time . However, the excitation of this large number of cardiomyocytes requires the application of HEF which reaches around 100 V/cm or higher in some regions of the myocardium . A HEF of this magnitude may lead to acute myocardial injury by electroporation , depression of contractile function  and blockage of electrical conduction by necrosis . Furthermore, our research team has already demonstrated that HEF of such intensity is able to kill cardiomyocytes [12, 13, 14]. Nevertheless, even a non-lethal HEF can make the cell unexcitable, generating a substrate to arrhythmia re-induction . These side effects might be related to the low survival rates reported after OHCA, which have been stable at 7–8% for the last 30 years despite the improvements in treatment and the increased availability of automated external defibrillators (AEDs) in public places [4, 16]. In this context, several studies have been carried out with the aim of improving defibrillation procedure to increase its success rate whilst reducing its side effects.
Our aim was to show the efficacy of a simple and feasible method able to improve the defibrillatory procedure, through the study of the strength–duration (SxD) curves. SxD curves have been exhaustively studied for the heart, but for the first time we present a paired study with heart pacing SxD curves and defibrillation SxD curves for the same hearts; from these data, we also propose a relationship between heart pacing electric field (E) and defibrillation HEF as a possible indicator of heart damage risk.
Also, a previous study of our research team has shown that the ratio of lethal HEF to excitation threshold for isolated rat cardiomyocytes changes with stimuli duration and is maximal for 0.5-ms stimuli , which indicates that this duration would probably be safer for defibrillation. In this study, we confirmed the relationship between defibrillation safety and pulse duration through SxD curves. We correlated the required HEF intensity for defibrillation with the shock intensity required for heart pacing to verify whether the existence of a previously observed optimum duration for cardiomyocyte stimulation would be translated to a higher efficiency in rat heart defibrillation.
Adult male Wistar rats were euthanized under deep anesthesia and the hearts were removed and cannulated in less than 30 s, avoiding physiological function loss due to prolonged ischemia [17, 18]. Hearts weighed on average 2.46 ± 0.07 g.
Defibrillation probability curves
Ratio of defibrillation probability to pacing threshold
The present study shows that, within certain limits, the longer the pulse duration is, the lower is the threshold intensity for pacing and defibrillation, as expected for the stimulation of excitable tissues [19, 20]. Herein, we show for the first time, to the best of our knowledge, the stimulation and defibrillation SxD curves for the same hearts, considering an applied E homogeneously, which generated values more reliable and preparation independent.
We observed the same behavior for SxD curves for pacing and for defibrillation. Pacing requires a small pulse strength to be successful, because when a small number of cells are excited, the action potential propagation occurs throughout the heart . Thus, only a small number of cells need to be submitted to a supra-threshold E. In contrast, for defibrillation, a simultaneous excitation of a large portion of the myocardium (75–90%)  is required to make the cells non-excitable for a period and to terminate the fibrillatory mechanisms.
During the E application, non-uniform potential gradient formation happens because the cardiac tissue is anisotropic, composed by muscle fibers oriented in multiple directions with layers of connective tissue [22, 23]. Also, the heart region subjected to a higher potential gradient is closer to the electrodes; consequently, this region is easily stimulated, while other regions might not be stimulated depending on the applied E strength. However, when a critical mass of cardiomyocytes must be depolarized at the same time, as in the case of defibrillation, E has to be increased to stimulate cells which are not close to the electrodes; as a result, defibrillatory E is much larger than ET [21, 24]. In addition, pacing occurs during diastole, when most ventricular myocytes are relaxed in a vulnerable period. However, during defibrillation, the myocytes are not synchronized, each group of cells may be in a different action potential phase, requiring even higher amplitudes to excite cells during their relative refractory period and then terminate the fibrillation wave fronts [22, 24]. Hence, during defibrillation, the closest regions to the electrodes are exposed to a much higher E than the ET. The transmembrane potential variation (ΔVm) of each myocyte is proportional to the applied E module , then the maximal ΔVm is observed in the near-electrode myocytes; moreover, during threshold pacing, we may assume that the maximal ΔVm in the myocytes of this region is the stimulation threshold (ΔVmT); as a result, it is constant and does not change according to stimuli duration . During defibrillation, the ΔVm can be expressed by HEFdefibrillatory/ET multiplied by the ΔVmT, where HEFdefibrillatory is the high-intensity electric field necessary to successful defibrillation, which means that the HEFdefibrillatory/ET could be taken as an indirect index of the induced ΔVm in the cardiomyocytes during defibrillation. This information is very important because it allows to infer which duration induced a lower ΔVm, since a high ΔVm may lead to electroporation and consequent cell death [27, 28]. We observed a lower HEFdefibrillatory/ET ratio (17.65) when we defibrillated with 0.5-ms pulses. Thus, using this pulse duration, the induced ΔVm in the cardiomyocytes was probably lower and, consequently, it may be safer to be used in defibrillation procedures.
Defibrillatory pulses with duration of 0.5-ms are probably better for defibrillating rat hearts since not only the HEF50 in ×Threshold is smaller, but cells are also less susceptible to injury for this duration . Although the defibrillation success × pulse duration depends on the animal study [24, 29], the use of a short pulse duration might improve defibrillation procedures in human hearts, as Semenov et al.  also argued, since the commercial defibrillators use pulses with 5- or 10-ms duration, i.e., near the rheobase [21, 22]. Despite the difference in heart size between rodents and human, a factor that can influence the cardiac arrest mechanisms , models using rodent hearts have several advantages as presented by Patten et al. . These models, such as the one used in this study, produce results that cannot be directly related to the clinical context, but that generate important results, especially on the understanding, diagnosis and treatment of conditions such as VF because of the unavailability of studies on human subjects for ethical reasons. However, due to the limitations of the models, for results of basic science to be translated into clinical practice, studies in larger mammals, whose heart size is more similar to that of humans, are needed.
A possible limitation of this work was the time between heart removal and cannulation finalization (30 s). However, it was not sufficient to cause ischemia impairment in previous studies [17, 18]; additionally, contractile and chronotropic impairment may be present due to prolonged experiment time and cumulative effect of consecutive shocks.
Despite the fact that the rat hearts were placed in a Langendorff-adapted preparation for a maximum time of 3 h and that this type of preparation leads to contractile and chronotropic function deterioration of the heart ranging from 5 to 10% per hour , we believe that the randomized choice of the pulse duration sequence could minimize changes in the outcomes that were implied by this deterioration. However, we did not note any significant change in the heart function during the experiments involving all hearts included in this work.
We hope that this work can bring important clinical implications in the future, leading to an optimization of commercial defibrillators only by changing the pulse duration. A simple reduction of the shock duration, even on a small scale, may possibly lead to a significant increase in the effectiveness of defibrillatory procedures.
Considering our results, it is possible to conclude that defibrillated rat hearts by 0.5-ms pulses are less likely to suffer from injuries since the relationship between defibrillation probability and pacing threshold was lower for this duration, indicating that the impairment is smaller because the induced potential is lower in this case.
This outcome, along with a greater stimulatory safety factor for the duration of 0.5-ms , supports the hypothesis that a defibrillatory shock with this duration would be better for reversing VF in rats. Still, further studies should be performed to identify possible mechanisms underlying this finding.
Materials and methods
The protocols for animal care and use were approved by the Institutional Committee for Ethics in Animal Research (IB/UNICAMP, No. 4355-1). All the animals received care in accordance with relevant guidelines and regulations.
Isolated heart preparation
After 10 min for heart rate stabilization, the cardiac electrophysiological signal (ECG) was captured by Ag/AgCl electrodes (ECG electrodes), amplified (gain = 2000) and filtered (high-pass filter: fch = 3 Hz; low-pass filter: fcl = 100 Hz) by a electrophysiological signal amplifier (developed and manufactured by the Center of Biomedical Engineering, Campinas, Brazil). The ECG trace was visualized in an oscilloscope (manufactured by Tektronix Inc. Beaverton, OR, USA, model TDS 2014C, 100 MHz bandwidth) (Fig. 7). The spontaneous heart rate was determined by measuring the interval between five ECG R-waves.
Stimulation electrodes were connected to a low-intensity electrical stimulator (LIS, developed and manufactured by Center for Biomedical Engineering, Campinas, Brazil). The pacing threshold was determined for seven pulse durations (0.2-, 0.5-, 1-, 3-, 5-, 8- and 10-ms, total wave duration). The pulse duration sequence was randomly chosen for each heart and the stimulus frequency was set to 20% above the measured spontaneous heart rate. The stimulus amplitude was increased until the heart rate was equalized with the stimulation rate; the heart rate was inferred through the use of a video signal edge detector (VED, developed and manufactured by the Center for Biomedical Engineering, Campinas, Brazil). VED was coupled to a video camera (Ikegami Tsushinki Co., LTD, Japan—ICD-31 mod.) and to a video monitor (Kodo Electronics Co, LTD, Seoul, Korea—mod. KBM1200S, Fig. 7). The voltage output of the VED was proportional to the displacement of the heart border. When the electrical output signal of the VED synchronized with the stimulatory pulses, we considered that the heart was being paced. The minimum electric field (E) that kept the synchronism was considered the ET. This protocol was repeated for each stimuli duration.
The fibrillator (developed and manufactured by the Center for Biomedical Engineering Center, Campinas, Brazil) was coupled to the stimulation electrodes and the VF was induced by delivering a sine wave signal, with 60 Hz, amplitude from 1 to 3 V/cm and duration from 0.5 to 2 s [10, 35]. Duration and stimuli amplitude were adjusted to induce VF which was detected by monitoring the ECG record. When VF was maintained for at least 2 min, it was considered sustained and the fibrillator was disconnected; otherwise, a new amplitude and duration combination was set and VF was re-induced.
Two SxD curves were obtained: pacing SxD curve was made with ET values and the defibrillation probability SxD curve was plotted with the average values of HEF50, in V/cm obtained from the survival analysis. Both SxD curves were adjusted by Weiss–Lapicque equation (Eq. 1).
The ratio of defibrillation probability to pacing threshold was plotted with the average values of HEF50, in ×Threshold obtained from the survival analysis.
Statistical significance index α adopted for all tests was 0.05. All analyses and tests were made with the software Prism 5.03 (GraphPad Software, San Diego, US).
The authors are grateful to the R&D team at CEB/UNICAMP and NMCE-Núcleo de Medicina e Cirurgia Experimental at Faculty of Medical Science-UNICAMP for the valuable technical support. This study was supported by CAPES (Coordination of Improvement of Higher Education Personnel, in Portuguese, scholarship to Priscila C. Antoneli) and FAPESP (Foundation for Research of the State of São Paulo, in Portuguese, Proc. N 2011/51199-6).
PCA: concept/design, data collection, data analysis/interpretation, statistics, drafting article, critical revision of article, and approval of article. JTG: drafting article, critical revision of article, and approval of article. IB: technical support and concept/design and approval of article. DDC: technical support and concept/design and approval of article. PXO: concept/design, data analysis/interpretation, drafting article, critical revision of article, and approval of article. All authors read and approved the final manuscript.
This study was supported by CAPES (Coordination of Improvement of Higher Education Personnel, in Portuguese, scholarship to Priscila C. Antoneli) and FAPESP (Foundation for Research of the State of São Paulo, in Portuguese, Proc. N 2011/51199-6).
Ethics approval and consent to participate
The protocols for animal care and use were approved by the Institutional Committee for Ethics in Animal Research (IB/UNICAMP, No. 4355-1).
Consent for publication
The authors declare that they have no competing interests.
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