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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.

No MeSH data available.


Related in: MedlinePlus

Validation of the proposed optogenetics-based strategy to quantify the efficiency of gene and cell therapy.(a,b) Schematics (for control and fully impaired cases, respectively) showing spatial distribution of normal/diseased tissue (left) and resulting activation patterns (right). (c) Zoomed-in views of the same maps as in (a), but for a case where excitability restoration was attempted via GD of INa to a subset of myocytes in a spatial pattern corresponding to GD-UL; therapeutic efficiency was calculated by comparing the total activation time to those for control (a) and fully impaired (b) cases, as described in the text. (d) Same as (c), but with excitability restored via delivery of INa-rich myocytes in a CD-UL spatial distribution. (e,f) Demonstration (for GD and CD, respectively) that the therapeutic efficiency of excitability restoration via delivery of INa to a particular set of cells is related by an inversely proportional power law to the optical energy required to excite optogenetically-transduced cells with an identical spatial pattern.
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f8: Validation of the proposed optogenetics-based strategy to quantify the efficiency of gene and cell therapy.(a,b) Schematics (for control and fully impaired cases, respectively) showing spatial distribution of normal/diseased tissue (left) and resulting activation patterns (right). (c) Zoomed-in views of the same maps as in (a), but for a case where excitability restoration was attempted via GD of INa to a subset of myocytes in a spatial pattern corresponding to GD-UL; therapeutic efficiency was calculated by comparing the total activation time to those for control (a) and fully impaired (b) cases, as described in the text. (d) Same as (c), but with excitability restored via delivery of INa-rich myocytes in a CD-UL spatial distribution. (e,f) Demonstration (for GD and CD, respectively) that the therapeutic efficiency of excitability restoration via delivery of INa to a particular set of cells is related by an inversely proportional power law to the optical energy required to excite optogenetically-transduced cells with an identical spatial pattern.

Mentions: We sought to demonstrate that the optical energy needed to excite light-sensitized cardiac tissue with a particular optogenetic configuration can be used to approximate the efficiency of restoring excitability via gene or cell delivery with the same spatial pattern. The developed in silico tools were used for this purpose. A “healthy” control model was created, with normal myocytes throughout (Fig. 8a), and an “impaired” case was also generated—with severely impaired excitability (10% of normal sodium current, INa) in a central disc-shaped region (2.5 mm diameter). The size of this central region approximated the island size for GD/CD-I expression patterns (see Fig. 2a,d). Activation sequences (right-hand side panels of Fig. 8a,b) resulting from electrical stimulation (same protocol as in Fig. 4) were constructed and in each case the activation time of the entire central region (AT) was obtained: ATctrl = 10.7 ms and ATimp = 19.1 ms for Fig. 8a,b, respectively. Reduced excitability caused a prominent decrease in CV, as evidenced by the local curvature of isochrones near the central region in Fig. 8b.


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)

Validation of the proposed optogenetics-based strategy to quantify the efficiency of gene and cell therapy.(a,b) Schematics (for control and fully impaired cases, respectively) showing spatial distribution of normal/diseased tissue (left) and resulting activation patterns (right). (c) Zoomed-in views of the same maps as in (a), but for a case where excitability restoration was attempted via GD of INa to a subset of myocytes in a spatial pattern corresponding to GD-UL; therapeutic efficiency was calculated by comparing the total activation time to those for control (a) and fully impaired (b) cases, as described in the text. (d) Same as (c), but with excitability restored via delivery of INa-rich myocytes in a CD-UL spatial distribution. (e,f) Demonstration (for GD and CD, respectively) that the therapeutic efficiency of excitability restoration via delivery of INa to a particular set of cells is related by an inversely proportional power law to the optical energy required to excite optogenetically-transduced cells with an identical spatial pattern.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f8: Validation of the proposed optogenetics-based strategy to quantify the efficiency of gene and cell therapy.(a,b) Schematics (for control and fully impaired cases, respectively) showing spatial distribution of normal/diseased tissue (left) and resulting activation patterns (right). (c) Zoomed-in views of the same maps as in (a), but for a case where excitability restoration was attempted via GD of INa to a subset of myocytes in a spatial pattern corresponding to GD-UL; therapeutic efficiency was calculated by comparing the total activation time to those for control (a) and fully impaired (b) cases, as described in the text. (d) Same as (c), but with excitability restored via delivery of INa-rich myocytes in a CD-UL spatial distribution. (e,f) Demonstration (for GD and CD, respectively) that the therapeutic efficiency of excitability restoration via delivery of INa to a particular set of cells is related by an inversely proportional power law to the optical energy required to excite optogenetically-transduced cells with an identical spatial pattern.
Mentions: We sought to demonstrate that the optical energy needed to excite light-sensitized cardiac tissue with a particular optogenetic configuration can be used to approximate the efficiency of restoring excitability via gene or cell delivery with the same spatial pattern. The developed in silico tools were used for this purpose. A “healthy” control model was created, with normal myocytes throughout (Fig. 8a), and an “impaired” case was also generated—with severely impaired excitability (10% of normal sodium current, INa) in a central disc-shaped region (2.5 mm diameter). The size of this central region approximated the island size for GD/CD-I expression patterns (see Fig. 2a,d). Activation sequences (right-hand side panels of Fig. 8a,b) resulting from electrical stimulation (same protocol as in Fig. 4) were constructed and in each case the activation time of the entire central region (AT) was obtained: ATctrl = 10.7 ms and ATimp = 19.1 ms for Fig. 8a,b, respectively. Reduced excitability caused a prominent decrease in CV, as evidenced by the local curvature of isochrones near the central region in Fig. 8b.

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