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A single-cell model of phase-driven control of ventricular fibrillation frequency.

ABSTRACT: The mechanisms controlling the rotation frequency of functional reentry in ventricular fibrillation (VF) are poorly understood. It has been previously shown that Ba2+ at concentrations up to 50 mumol/L slows the rotation frequency in the intact guinea pig (GP) heart, suggesting a role of the inward rectifier current (I(K1)) in the mechanism governing the VF response to Ba2+. Given that other biological (e.g., sinoatrial node) and artificial systems display phase-locking behavior, we hypothesized that the mechanism for controlling the rotation frequency of a rotor by I(K1) blockade is phase-driven, i.e., the phase shift between transmembrane current and voltage remains constant at varying levels of I(K1) blockade. We measured whole-cell admittance in isolated GP myocytes and in transfected human embryonic kidney (HEK) cells stably expressing Kir 2.1 and 2.3 channels. The admittance phase, i.e., the phase difference between current and voltage, was plotted versus the frequency in control conditions and at 10 or 50 micromol/L Ba2+ (in GP heart cells) or 1 mM Ba2+ (in HEK cells). The horizontal distance between plots was called the "frequency shift in a single cell" and analyzed. The frequency shift in a single cell was -14.14 +/- 5.71 Hz (n = 14) at 10 microM Ba2+ and -18.51 +/- 4.00 Hz (n = 10) at 50 microM Ba2+, p < 0.05. The values perfectly matched the Ba2+-induced reduction of VF frequency observed previously in GP heart. A similar relationship was found in the computer simulations. The phase of Ba2+-sensitive admittance in GP cells was -2.65 +/- 0.32 rad at 10 Hz and -2.79 +/- 0.26 rad at 30 Hz. In HEK cells, the phase of Ba2+-sensitive admittance was 3.09 +/- 0.03 rad at 10 Hz and 3.00 +/- 0.17 rad at 30 Hz. We have developed a biological single-cell model of rotation-frequency control. The results show that although rotation frequency changes as a result of I(K1) blockade, the phase difference between transmembrane current and transmembrane voltage remains constant, enabling us to quantitatively predict the change of VF frequency resulting from I(K1) blockade, based on single-cell measurement.

SUBMITTER: Grzeda KR

PROVIDER: S-EPMC2711310 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Molecular mechanisms responsible for 24 h circadian oscillations, entrainment to external cues, encoding of day length and the time-of-day effects have been well studied experimentally. However, it is still debated from the molecular network point of view whether each cell in suprachiasmatic nuclei harbors two molecular oscillators, where one tracks dawn and the other tracks dusk activities. A single cell dual morning and evening oscillator was proposed by Daan et al., based on the molecular network that has two sets of similar non-redundant per1/cry1 and per2/cry2 circadian genes and each can independently maintain their endogenous oscillations. Understanding of dual oscillator dynamics in a single cell at molecular level may provide insight about the circadian mechanisms that encodes day length variations and its response to external zeitgebers. We present here a realistic dual oscillator model of circadian rhythms based on the series of hypotheses proposed by Daan et al., in which they conjectured that the circadian genes per1/cry1 track dawn while per2/cry2 tracks dusk and they together constitute the morning and evening oscillators (dual oscillator). Their hypothesis also provides explanations about the encoding of day length in terms of molecular mechanisms of per/cry expression. We frame a minimal mathematical model with the assumption that per1 acts a morning oscillator and per2 acts as an evening oscillator and to support and interpret this assumption we fit the model to the experimental data of per1/per2 circadian temporal dynamics, phase response curves (PRC's), and entrainment phenomena under various light-dark conditions. We also capture different patterns of splitting phenomena by coupling two single cell dual oscillators with neuropeptides vasoactive intestinal polypeptide (VIP) and arginine vasopressin (AVP) as the coupling agents and provide interpretation for the occurrence of splitting in terms of ME oscillators, though they are not required to explain the morning and evening oscillators. The proposed dual oscillator model based on Daan's hypothesis supports per1 and per2 playing the role of morning and evening oscillators respectively and this may be the first step towards the understanding of the core molecular mechanism responsible for encoding the day length.

Project description:IntroductionMost animal studies of ventricular fibrillation (VF) waveform characteristics involve healthy animals with VF initiated by electric shock. However, clinical VF is usually the result of ischemia. The waveform characteristics in these two types of VF may differ. The angular velocity (AV), frequency ratio (FR) and median frequency (MF) are three frequency-based measures of VF. The scaling exponent (ScE), the logarithm of the absolute correlations (LAC) and the Hurst exponent (HE) are three measures of the fractal dimension of VF.HypothesisWe hypothesized that these quantitative measures would differ between ischemic and electrically initiated VF.MethodsVF was induced in 14 swine by electric shock and in 12 swine by ischemia. For ischemia induced VF animals, an angioplasty catheter was positioned in the mid-LAD and the balloon inflated. A mean of 891+/-608 (S.D.)s later, VF occurred. For electrically induced animals, an AC current was passed through a catheter in the RV. Following initiation by either method, VF was recorded for 7min. Sequential 5s epochs were analyzed for AV, FR, MF and fractal dimension measures.ResultsIschemic VF demonstrated a significantly higher fractal dimension as estimated by the ScE for the first 0-90s (p=0.021) and for 90-180s (p=0.016). The Hurst exponent was significantly higher for ischemic VF for both 0-90s (p<0.0001) and 90-180s (p<0.0001). The fractal dimension as estimated by the LAC method was not significantly different for 0-90s (p=0.056) but was highly significant for 90-180s (p=0.001). During the initial 90s the groups did differ in all measures of frequency as follows: AV (p<0.001), FR (p<0.001), MF (p<0.001). These differences did not persist beyond 90s except for a mild elevation of the FR after 270s (p<0.02).ConclusionFractal based measures indicate an increase in the fractal dimension of ischemia induced VF for the first 180s when compared to electrically induced VF. Frequency-based measures uniformly demonstrate a pattern of higher frequencies for electrically induced VF for the first 90s. The increased fractal dimension and decreased frequencies associated with ischemia induced VF may reflect changes in the underlying myocardial physiology that can be used to guide therapies.

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A single-cell model of phase-driven control of ventricular fibrillation frequency.

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