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Optogenetic determination of the myocardial requirements for extrasystoles by cell type-specific targeting of ChannelRhodopsin-2
- Source :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Year :
- 2015
-
Abstract
- Extrasystoles lead to several consequences, ranging from uneventful palpitations to lethal ventricular arrhythmias, in the presence of pathologies, such as myocardial ischemia. The role of working versus conducting cardiomyocytes, as well as the tissue requirements (minimal cell number) for the generation of extrasystoles, and the properties leading ectopies to become arrhythmia triggers (topology), in the normal and diseased heart, have not been determined directly in vivo. Here, we used optogenetics in transgenic mice expressing ChannelRhodopsin-2 selectively in either cardiomyocytes or the conduction system to achieve cell type-specific, noninvasive control of heart activity with high spatial and temporal resolution. By combining measurement of optogenetic tissue activation in vivo and epicardial voltage mapping in Langendorff-perfused hearts, we demonstrated that focal ectopies require, in the normal mouse heart, the simultaneous depolarization of at least 1,300–1,800 working cardiomyocytes or 90–160 Purkinje fibers. The optogenetic assay identified specific areas in the heart that were highly susceptible to forming extrasystolic foci, and such properties were correlated to the local organization of the Purkinje fiber network, which was imaged in three dimensions using optical projection tomography. Interestingly, during the acute phase of myocardial ischemia, focal ectopies arising from this location, and including both Purkinje fibers and the surrounding working cardiomyocytes, have the highest propensity to trigger sustained arrhythmias. In conclusion, we used cell-specific optogenetics to determine with high spatial resolution and cell type specificity the requirements for the generation of extrasystoles and the factors causing ectopies to be arrhythmia triggers during myocardial ischemia.
- Subjects :
- Male
Cardiac Complexes, Premature
Myocardial Ischemia
Channelrhodopsin
030204 cardiovascular system & hematology
Arrhythmias
Inbred C57BL
Transgenic
Connexins
Cardiac Complexes
Mice
0302 clinical medicine
Myocytes, Cardiac
0303 health sciences
Multidisciplinary
Depolarization
Heart
Coronary Vessels
Arrhythmia
Cardiac ectopies
Optogenetics
Purkinje fiber
Animals
Arrhythmias, Cardiac
Electrophysiological Phenomena
Humans
Integrases
Ligation
Mice, Inbred C57BL
Mice, Transgenic
Myocardium
Purkinje Fibers
Rhodopsin
Organ Specificity
medicine.anatomical_structure
PNAS Plus
Cardiology
cardiovascular system
Electrical conduction system of the heart
Cardiac
Genetically modified mouse
medicine.medical_specialty
Cell type
Purkinje fibers
Biology
03 medical and health sciences
Channelrhodopsins
In vivo
Internal medicine
medicine
Premature
030304 developmental biology
Myocytes
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....86e142ae4471506e96a3b9818bbe9e38