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Optogenetics-enabled assessment of viral gene and cell therapy for restoration of cardiac excitability.

Ambrosi CM, Boyle PM, Chen K, Trayanova NA, Entcheva E - Sci Rep (2015)

Bottom Line: Multiple cardiac pathologies are accompanied by loss of tissue excitability, which leads to a range of heart rhythm disorders (arrhythmias).Taken directly, these results can help guide optogenetic interventions for light-based control of cardiac excitation.More generally, our findings can help optimize gene therapy for restoration of cardiac excitability.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY.

ABSTRACT
Multiple cardiac pathologies are accompanied by loss of tissue excitability, which leads to a range of heart rhythm disorders (arrhythmias). In addition to electronic device therapy (i.e. implantable pacemakers and cardioverter/defibrillators), biological approaches have recently been explored to restore pacemaking ability and to correct conduction slowing in the heart by delivering excitatory ion channels or ion channel agonists. Using optogenetics as a tool to selectively interrogate only cells transduced to produce an exogenous excitatory ion current, we experimentally and computationally quantify the efficiency of such biological approaches in rescuing cardiac excitability as a function of the mode of application (viral gene delivery or cell delivery) and the geometry of the transduced region (focal or spatially-distributed). We demonstrate that for each configuration (delivery mode and spatial pattern), the optical energy needed to excite can be used to predict therapeutic efficiency of excitability restoration. Taken directly, these results can help guide optogenetic interventions for light-based control of cardiac excitation. More generally, our findings can help optimize gene therapy for restoration of cardiac excitability.

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Related in: MedlinePlus

Threshold optical energy as a measure of excitability in optogenetically-modified cardiac syncytia.Strength-duration relationships for in vitro monolayers with light-sensitivity inscribed by (a) GD and (b) CD (n = 5–17 for pulse widths 2–90 ms). Analogous strength-duration relationships for in silico monolayers with light-sensitivity inscribed by (c) GD and (d) CD (n = 5 for pulse widths 1–180 ms). (e,f) Averaged in vitro and in silico rheobase values derived from optical strength-duration curves in (a–f).
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f6: Threshold optical energy as a measure of excitability in optogenetically-modified cardiac syncytia.Strength-duration relationships for in vitro monolayers with light-sensitivity inscribed by (a) GD and (b) CD (n = 5–17 for pulse widths 2–90 ms). Analogous strength-duration relationships for in silico monolayers with light-sensitivity inscribed by (c) GD and (d) CD (n = 5 for pulse widths 1–180 ms). (e,f) Averaged in vitro and in silico rheobase values derived from optical strength-duration curves in (a–f).

Mentions: For each combination of transgene delivery mode and spatial pattern, we used light pulses with controlled irradiance levels to identify the threshold for optical excitation, both in vitro and in silico. This allowed us to quantitatively characterize the relationship between transgene properties and the efficiency of gene or cell therapy (e.g., for restoration of excitability). In vitro strength-duration curves were constructed for pulse widths ranging from 2 to 90 ms with irradiance values of up to 0.6 mW/mm2 (CD-UL) (Fig. 6). For GD (Fig. 6a), optical excitation thresholds were higher for the island configuration (GD-I) than for uniform distributions (GD-UL and GD-UH). That is, a localized GD distribution did not yield any special advantages and, for uniform patterns, maximizing opsin density in GD monotonically increased optical excitability. Notably, the proportion of ChR2-expressing cells in GD-UH configurations (approximately 71%, Fig. 3c) was greater than that in the densest areas of GD-I patterns (approximately 62%, Fig. 3a), which provides a direct explanation for the fact that the latter were less optically excitable than the former. Generally speaking, GD-UL configurations had lower excitation thresholds than GD-I patterns, even though their overall proportion of light-sensitive cells was lower (approximately 36%, Fig. 3b); this suggests that distribution of ChR2-rich cells throughout the illuminated area instead of a compact central region resulted in a configuration that was less susceptible to source-sink mismatch effects during optogenetic stimulation.


Optogenetics-enabled assessment of viral gene and cell therapy for restoration of cardiac excitability.

Ambrosi CM, Boyle PM, Chen K, Trayanova NA, Entcheva E - Sci Rep (2015)

Threshold optical energy as a measure of excitability in optogenetically-modified cardiac syncytia.Strength-duration relationships for in vitro monolayers with light-sensitivity inscribed by (a) GD and (b) CD (n = 5–17 for pulse widths 2–90 ms). Analogous strength-duration relationships for in silico monolayers with light-sensitivity inscribed by (c) GD and (d) CD (n = 5 for pulse widths 1–180 ms). (e,f) Averaged in vitro and in silico rheobase values derived from optical strength-duration curves in (a–f).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664892&req=5

f6: Threshold optical energy as a measure of excitability in optogenetically-modified cardiac syncytia.Strength-duration relationships for in vitro monolayers with light-sensitivity inscribed by (a) GD and (b) CD (n = 5–17 for pulse widths 2–90 ms). Analogous strength-duration relationships for in silico monolayers with light-sensitivity inscribed by (c) GD and (d) CD (n = 5 for pulse widths 1–180 ms). (e,f) Averaged in vitro and in silico rheobase values derived from optical strength-duration curves in (a–f).
Mentions: For each combination of transgene delivery mode and spatial pattern, we used light pulses with controlled irradiance levels to identify the threshold for optical excitation, both in vitro and in silico. This allowed us to quantitatively characterize the relationship between transgene properties and the efficiency of gene or cell therapy (e.g., for restoration of excitability). In vitro strength-duration curves were constructed for pulse widths ranging from 2 to 90 ms with irradiance values of up to 0.6 mW/mm2 (CD-UL) (Fig. 6). For GD (Fig. 6a), optical excitation thresholds were higher for the island configuration (GD-I) than for uniform distributions (GD-UL and GD-UH). That is, a localized GD distribution did not yield any special advantages and, for uniform patterns, maximizing opsin density in GD monotonically increased optical excitability. Notably, the proportion of ChR2-expressing cells in GD-UH configurations (approximately 71%, Fig. 3c) was greater than that in the densest areas of GD-I patterns (approximately 62%, Fig. 3a), which provides a direct explanation for the fact that the latter were less optically excitable than the former. Generally speaking, GD-UL configurations had lower excitation thresholds than GD-I patterns, even though their overall proportion of light-sensitive cells was lower (approximately 36%, Fig. 3b); this suggests that distribution of ChR2-rich cells throughout the illuminated area instead of a compact central region resulted in a configuration that was less susceptible to source-sink mismatch effects during optogenetic stimulation.

Bottom Line: Multiple cardiac pathologies are accompanied by loss of tissue excitability, which leads to a range of heart rhythm disorders (arrhythmias).Taken directly, these results can help guide optogenetic interventions for light-based control of cardiac excitation.More generally, our findings can help optimize gene therapy for restoration of cardiac excitability.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY.

ABSTRACT
Multiple cardiac pathologies are accompanied by loss of tissue excitability, which leads to a range of heart rhythm disorders (arrhythmias). In addition to electronic device therapy (i.e. implantable pacemakers and cardioverter/defibrillators), biological approaches have recently been explored to restore pacemaking ability and to correct conduction slowing in the heart by delivering excitatory ion channels or ion channel agonists. Using optogenetics as a tool to selectively interrogate only cells transduced to produce an exogenous excitatory ion current, we experimentally and computationally quantify the efficiency of such biological approaches in rescuing cardiac excitability as a function of the mode of application (viral gene delivery or cell delivery) and the geometry of the transduced region (focal or spatially-distributed). We demonstrate that for each configuration (delivery mode and spatial pattern), the optical energy needed to excite can be used to predict therapeutic efficiency of excitability restoration. Taken directly, these results can help guide optogenetic interventions for light-based control of cardiac excitation. More generally, our findings can help optimize gene therapy for restoration of cardiac excitability.

No MeSH data available.


Related in: MedlinePlus