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Research Papers

Acute Optogenetic Modulation of Cardiac Twitch Dynamics Explored Through Modeling

[+] Author and Article Information
Yasser Aboelkassem

Institute for Computational Medicine,
Department of Biomedical Engineering,
Johns Hopkins University,
Baltimore, MD 21218
e-mail: yasser@jhu.edu

Stuart G. Campbell

Department of Biomedical Engineering,
Yale University,
New Haven, CT 06511
e-mail: stuart.campbell@yale.edu

Manuscript received May 19, 2016; final manuscript received September 1, 2016; published online October 21, 2016. Assoc. Editor: Jessica E. Wagenseil.

J Biomech Eng 138(11), 111005 (Oct 21, 2016) (11 pages) Paper No: BIO-16-1206; doi: 10.1115/1.4034655 History: Received May 19, 2016; Revised September 01, 2016

Optogenetic approaches allow cellular membrane potentials to be perturbed by light. When applied to muscle cells, mechanical events can be controlled through a process that could be termed “optomechanics.” Besides functioning as an optical on/off switch, we hypothesized that optomechanical control could include the ability to manipulate the strength and duration of contraction events. To explore this possibility, we constructed an electromechanical model of the human ventricular cardiomyocyte while adding a representation of channelrhodopsin-2 (ChR2), a light-activated channel commonly used in optogenetics. Two hybrid stimulus protocols were developed that combined light-based stimuli with traditional electrical current (all-or-none) excitation. The first protocol involved delivery of a subthreshold optical stimulus followed 50–90 ms later by an electrical stimulus. The result was a graded inhibition of peak cellular twitch force in concert with a prolongation of the intracellular Ca2+ transient. The second protocol was comprised of an electrical stimulus followed by a long light pulse (250–350 ms) that acted to prolong the cardiac action potential (AP). This created a pulse duration-dependent prolongation of the intracellular Ca2+ transient that in turn altered the rate of muscle relaxation without changing peak twitch force. These results illustrate the feasibility of acute, optomechanical manipulation of cardiomyocyte contraction and suggest that this approach could be used to probe the dynamic behavior of the cardiac sarcomere without altering its intrinsic properties. Other experimentally meaningful stimulus protocols could be designed by making use of the optomechanical cardiomyocyte model presented here.

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References

Figures

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Fig. 1

Schematic diagram of a human cardiac ventricular myocyte model that includes cellular electrophysiology, myofilament contractile function, and light-activated ion channels. An electrophysiological model representing a human epicardial myocyte [24] was coupled to models of ChR2 [21] and myofilament mechanics [25]. The equations representing each model component were merged into a single system and solved simultaneously to enable simulations of light-activated mechanical events.

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Fig. 2

Hybrid stimulation protocols involving a combination of light and electrical current. (a) In protocol 1, an initial light pulse is followed by electrical current stimulus. The delay between light initiation and electrical stimulus was set to tSE1 = 50, 70, or 90 ms. The voltage traces in this panel show how the cell responds to each of the stimuli when they are applied separately. (b) In protocol 2, a depolarizing electric current stimulus was followed by light pulses of varying duration, including tDL = 250, 300, or 350 ms. As in panel A, the voltage traces illustrate responses that occur when the two stimuli are applied on their own.

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Fig. 3

Simulation of protocol 1 within a train of normally stimulated beats. A series of five beats was simulated. Beats 1, 2, 4, and 5 were elicited by a 3 ms, 10 mW/mm2 light pulse. Protocol 1 was executed only on beat 3 (indicated by the shaded events), consisting of a 3 ms subthreshold optical stimulus (intensity 0.111 mW/mm2) followed 70 ms later by an electrical current pulse. Membrane voltage (a), intracellular Ca2+ (b), and relative contractile force (c) are plotted over time.

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Fig. 4

Effect of varying the delay between optical and electrical current stimuli under protocol 1. The delay interval used in each simulation is indicated by the trace color, as shown in the legend. Each perturbation is compared to a baseline electrically stimulated event. Membrane voltage (a), intracellular Ca2+ (b), and relative contractile force (c) are plotted over time for each condition. Ca2+-force phase loops indicate the ability of delay intervals to probe Ca2+-contraction dynamics (d). The time course of sarcomere shortening under each delay interval is also shown (e).

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Fig. 5

Ion currents predicted by the model in response to varying delay intervals under protocol 1. The delay interval used in each simulation is indicated by the trace color, as shown in the legend. Each perturbation is compared to a baseline electrically stimulated event. Note that varying time and current scales are used in each panel to better view the details of each current type. INa (a), ICa (b), Ito1 (c), INaCa (d), and INaK (e) are shown.

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Fig. 6

Additional ion currents predicted by the model in response to varying delay intervals under protocol 1. The delay interval used in each simulation is indicated by the trace color, as shown in the legend. Each perturbation is compared to a baseline electrically stimulated event. Note that varying time and current scales are used in each panel to better view the details of each current type. IKr (a), IKs (b), ICa,K (c), IK1 (d), and IChR2 (e) are shown.

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Fig. 7

Simulation of protocol 2 within a train of normally stimulated beats. A series of five beats was simulated: beats 1, 2, 4, and 5 were elicited by a 0.5 ms, −100 μA/μF pulse; protocol 2 was executed only on beat 3 (indicated by the shaded events), consisting of the same electrical current stimulus followed 0.25 ms later by a 300 ms light pulse with an intensity of 0.033 mW/mm2. Membrane voltage (a), intracellular Ca2+ (b), and relative contractile force (c) are plotted over time.

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Fig. 8

Effect of varying the duration of the light pulse following electrical current stimulus under protocol 2. The light pulse duration used in each simulation is indicated by the trace color, as shown in the legend. Each perturbation is compared to a baseline electrically stimulated event. Membrane voltage (a), intracellular Ca2+ (b), and relative contractile force (c) are plotted over time for each condition. Ca2+-force phase loops indicate the ability of the light pulse duration to probe Ca2+-contraction dynamics (d). The time course of sarcomere shortening under each pulse duration is also shown (e).

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Fig. 9

Ion currents predicted by the model in response to varying the duration of the light pulse following electrical current stimulus under protocol 2. The light pulse duration used in each simulation is indicated by the trace color, as shown in the legend. Each perturbation is compared to a baseline electrically stimulated event. Note that varying time and current scales are used in each panel to better view the details of each current type. INa (a), ICa (b), Ito1 (c), INaCa (d), and INaK (e) are shown.

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Fig. 10

Additional ion currents predicted by the model in response to varying the duration of the light pulse following electrical current stimulus under protocol 2. The light pulse duration used in each simulation is indicated by the trace color, as shown in the legend. Each perturbation is compared to a baseline electrically stimulated event. Note that varying time and current scales are used in each panel to better view the details of each current type. IKr (a), IKs (b), ICaK (c), IK1 (d), and IChR2 (e) are shown.

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Fig. 11

Summary of protocol 1 and 2 effects on properties of the twitch force. By altering the interval between stimuli (tSE under protocol 1), it was possible to alter peak twitch force (a) and the time from peak force to 50 and 75% relaxation (T50 and T75, respectively) (b). Under protocol 2, the duration of the light pulse after electrical current stimulus (tDL) also yielded targeted alterations in T50 and T75.

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