cellular calcium signaling in cardiac arrhythmias · 2014-12-19 · cellular calcium signaling in...
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![Page 1: Cellular calcium signaling in cardiac arrhythmias · 2014-12-19 · Cellular calcium signaling in cardiac arrhythmias Crystal M. Ripplinger, Ph.D. Assistant Professor Department of](https://reader034.vdocuments.site/reader034/viewer/2022050109/5f46ea7cbe27b638da3707ca/html5/thumbnails/1.jpg)
Cellular calcium signaling in cardiac arrhythmias
Crystal M. Ripplinger, Ph.D.
Assistant Professor
Department of Pharmacology, UC Davis
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• Leading cause of death in the industrialized world• Due to many different underlying causes
Sudden Cardiac Death - Ventricular Arrhythmia
IschemicCoronary artery disease
Non-IschemicValvular disease
Hypertension
GeneticCardiomyopathy / Channelopathy
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Multi-Scale Approaches
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Arrhythmia Research at UC Davis
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Whole Organism:Chiamvimonvat,Chen, Ripplinger
Whole Heart:Ripplinger
Cellular/Sub-cellular:Bers, Bossuyt,
Chen-Izu, Xiang,Chiamvimonvat
Protein:Sack, Yarov-Yarovoy
Computational:Clancy, Grandi,
Izu, Sato
![Page 5: Cellular calcium signaling in cardiac arrhythmias · 2014-12-19 · Cellular calcium signaling in cardiac arrhythmias Crystal M. Ripplinger, Ph.D. Assistant Professor Department of](https://reader034.vdocuments.site/reader034/viewer/2022050109/5f46ea7cbe27b638da3707ca/html5/thumbnails/5.jpg)
Arrhythmia Research at UC Davis
Co
mp
uta
tio
nal
Ap
pro
ach
es
Whole Organism:Chiamvimonvat,Chen, Ripplinger
Whole Heart:Ripplinger
Cellular/Sub-cellular:Bers, Bossuyt,
Chen-Izu, Xiang,Chiamvimonvat
Protein:Sack, Yarov-Yarovoy
Computational:Clancy, Grandi,
Izu, Sato
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Excitation-Contraction Coupling:Cellular Level
Bers DM (2010) Nature.
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Excitation-Contraction Coupling: Whole HeartDual Optical Imaging of Vm and Ca2+
Excitation-Contraction
Uncoupler:
Blebbistatin (~10 μM)
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082010
Vm
Fluorescence
Ca2+
Fluorescence
ECG
- Vm
- Ca2+
Dual Optical Imaging of Vm and Ca2+
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Dual Optical Imaging of Vm and Ca2+
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Cardiac Sympathetic Nerves
Batulevicius et al.,Auton Neurosci, 2008
Saburkina et al.,Heart Rhythm, 2010
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Altered Sympathetic Activity and Arrhythmia
Li, AJP 2003
Hyper/De-nervationfollowing MI
Hyperinnervationwith high cholesterol
CON
HC
Liu, CircRes 2003
Altered sympathetic activity in patients with
ICD shocks
Boogers, JACC 2010
Chen, CV Res 2001
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How does sympathetic activity trigger
arrhythmia?Isolated cardiac
myocyte
Isolated Cell
IntactHeart
?Pogwizd and Bers, Circ Res 2001
Norepinephrine
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So Little Source, So Much Sink: Requirements for
Afterdepolarizations to Propagate in TissueYuanfang Xie, Daisuke Sato, Alan Garfinkel, Zhilin Qu, James N. Weiss,
Biophys J. 2010
# o
f c
ell
s
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20
40
60
80
100
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2000
4000
6000
8000
10000
0
55000200000
400000
600000
800000
1000000Normal
Cellular HF
Cellular HF + uncoupling
1D 2D 3D
~5000 cells
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Protocol: Apply controlled local sympathetic stimulation to the intact heart
Normal Rabbit HeartVarying doses ofNorepinephrine (NE)Low Dose: 30 – 120 μMHigh Dose: 125 – 250 μMControl: Normal Tyrode’s
LV
RV
Can localized β-AR stimulation produce spatio-
temporal synchronization of SR Ca2+ release to
produce propagating PVCs in the intact heart?
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NE–induced PVCs
Myles et al, Circ Res, 2012.
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NE–induced PVCs
Vm
Fluorescence
PVCs
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Mechanism of PVCs: SR Ca2+ release
Myles et al, Circ Res, 2012. Vm Vm
Ca2+
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Quantify Area of Exposure to NE
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Right Ventricle requires less area of NE
exposure to trigger SR Ca2+ release
~2D vs. 3D Tissue Geometry
Myles et al, Circ Res, 2012.
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How many Myocytes are in short Vm- Ca2+ delay zone
(and may trigger PVC)?
Quasi-2D/RV
Epi
Endo
Epi
Endo
Area of
source-sink
Interaction
12,200 cells 2 x 106 cells
3D/LV
Experimental
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How many Myocytes are in short Vm- Ca2+ delay zone
(and may trigger PVC)?
Quasi-2D/RV
Epi
Endo
Epi
Endo
Area of
source-sink
Interaction
12,200 cells 2 x 106 cells
3D/LV
Experimental
Theoretical (Xie, Sato, Garfinkel, Zu & Weiss, 2010)
0
2,000
4,000
6,000
8,000
10,000 2D RV?
HF HF +
Uncoupl
Co
ntr
ol
10
100
1,000
10,000
100,000
1,000,000 3D LV?
Co
ntr
ol
HF
HF
+U
nco
up
l
30,000
5,000
817,280 cells7,854 cells
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Summary
Integrative approach – building on cellular-level and computational datasets to understand how pathological calcium handling leads to arrhythmia at the whole-heart level
Whole-heart data, in turn, validates and confirms cellular and computational findings
Ongoing studies:
Determine the impact of HF remodeling on localized β-AR-induced PVCs
UC Davis Rabbit Model of Non-Ischemic Heart Failure – currently used by ~8 labs, ~30 different experiments/animal
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People:
• Rachel Myles, MD, PhD
• Lianguo Wang, MD
• Chaoyi Kang
• Nicole De Jesus
• Shannon Murphy, PhD
Collaborators: Dr. Don Bers,
Dr. Daisuke Sato
Acknowledgements:Funding:
• NIH: R01 HL111600
• AHA : SDG 9010015
• NIH: P30 HL101280
• UC Davis CTSC