TY - JOUR
T1 - Critical Requirements for the Initiation of a Cardiac Arrhythmia in Rat Ventricle
T2 - How Many Myocytes?
AU - Ullah, Aman
AU - Hoang-Trong, Minhtuan
AU - Lederer, Williamjonathan
AU - Winslow, Raimondl
AU - Jafri, Mohsin Saleet
N1 - Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/6/1
Y1 - 2022/6/1
N2 - Cardiovascular disease is the leading cause of death worldwide due in a large part to arrhythmia. In order to understand how calcium dynamics play a role in arrhythmogenesis, normal and dysfunctional Ca2+ signaling in a subcellular, cellular, and tissued level is examined using cardiac ventricular myocytes at a high temporal and spatial resolution using multiscale computational modeling. Ca2+ sparks underlie normal excitation–contraction coupling. However, under pathological conditions, Ca2+ sparks can combine to form Ca2+ waves. These propagating elevations of (Ca2+)i can activate an inward Na+–Ca2+ exchanger current (INCX) that contributes to early after-depolarization (EADs) and delayed after-depolarizations (DADs). However, how cellular currents lead to full depolarization of the myocardium and how they initiate extra systoles is still not fully understood. This study explores how many myocytes must be entrained to initiate arrhythmogenic depolarizations in biophysically detailed computational models. The model presented here suggests that only a small number of myocytes must activate in order to trigger an arrhythmogenic propagating action potential. These conditions were examined in 1-D, 2-D, and 3-D considering heart geometry. The depolarization of only a few hundred ventricular myocytes is required to trigger an ectopic depolarization. The number decreases under disease conditions such as heart failure. Furthermore, in geometrically restricted parts of the heart such as the thin muscle strands found in the trabeculae and papillary muscle, the number of cells needed to trigger a propagating depolarization falls even further to less than ten myocytes.
AB - Cardiovascular disease is the leading cause of death worldwide due in a large part to arrhythmia. In order to understand how calcium dynamics play a role in arrhythmogenesis, normal and dysfunctional Ca2+ signaling in a subcellular, cellular, and tissued level is examined using cardiac ventricular myocytes at a high temporal and spatial resolution using multiscale computational modeling. Ca2+ sparks underlie normal excitation–contraction coupling. However, under pathological conditions, Ca2+ sparks can combine to form Ca2+ waves. These propagating elevations of (Ca2+)i can activate an inward Na+–Ca2+ exchanger current (INCX) that contributes to early after-depolarization (EADs) and delayed after-depolarizations (DADs). However, how cellular currents lead to full depolarization of the myocardium and how they initiate extra systoles is still not fully understood. This study explores how many myocytes must be entrained to initiate arrhythmogenic depolarizations in biophysically detailed computational models. The model presented here suggests that only a small number of myocytes must activate in order to trigger an arrhythmogenic propagating action potential. These conditions were examined in 1-D, 2-D, and 3-D considering heart geometry. The depolarization of only a few hundred ventricular myocytes is required to trigger an ectopic depolarization. The number decreases under disease conditions such as heart failure. Furthermore, in geometrically restricted parts of the heart such as the thin muscle strands found in the trabeculae and papillary muscle, the number of cells needed to trigger a propagating depolarization falls even further to less than ten myocytes.
KW - Arrhythmia
KW - Computational model
KW - Heart failure
KW - Ventricular myocyte network
UR - http://www.scopus.com/inward/record.url?scp=85132687562&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85132687562&partnerID=8YFLogxK
U2 - 10.3390/cells11121878
DO - 10.3390/cells11121878
M3 - Article
C2 - 35741007
AN - SCOPUS:85132687562
SN - 2073-4409
VL - 11
JO - Cells
JF - Cells
IS - 12
M1 - 1878
ER -