Transcript Effects of Reduce Gap Junctional Conductance

BENG 230C
Cardiovascular Physiology
Cardiac Impulse Conduction
Including slides courtesy
Professor Wayne Giles
University of Calgary
Reading
Levy and Pappano, Chapter 3
Kléber AG, Rudy Y (2004)
Basic mechanisms of cardiac impulse
propagation and associated arrhythmias.
Physiol Rev. Apr;84(2):431-88. Review.
Willem Einthoven (1860-1927)
1903: Invented ECG machine
1924: Received Nobel Prize in Medicine
Sinus Node and the Purkinje System
of the Heart
Note:
1) Myogenic spontaneous pacing
2) Pattern of conduction
3) Apex and base of
the ventricle
1) Purkinje system
2) Transmural conduction
Adapted from figure 10-1, Guyton & Hall
Cardiac Conduction Sequence
Electrocardiogram (ECG)


Conduction of electrical impulses through the heart
Measures and records intensity (millivolts) and the time intervals involved
Conventional Arrangement of Electrodes for
Recording Electrocardiogram
Adapted from figure 11-6, Guyton & Hall
Conventional Arrangement of Electrodes for
Recording Electrocardiogram
Adapted from figure 11-6, Guyton & Hall
ECG Leads
12 Lead ECG
V1-6 are precordial (chest) leads
The Important Deflections and Intervals of
a Typical Scalar Electrocardiogram
Adapted from figure 22-33, Berne & Levy
Organization of Cardiac Muscle Fibers
The Electrophysiological Syncytium
‘Intercellular Communication’
Adapted from figure 9-8, Sherwood
Cardiac Gap Junctions
Intercellular current flow in mammalian
ventricle
Cable Equation for Continuous
Propagation
Wavefront Propagating Towards a Boundary
Currents reflected from boundary reduce electrical load on cells proximal to
the boundary
Effects of wavefront collision on the upstroke of the transmembrane action potential and the
Na+ inward current. Top left: change of membrane potential (Vm) during action potential
upstroke. Bottom left: maximal upstroke velocity of transmembrane action potential in V/s.
Top right: Na+ inward current (INa). Bottom right: Na+ conductance (gNa). From Spach and
Kootsey
Dispersion of local current at front of propagating wave
current-to-load mismatch reduces current density, locally slows AP upstroke
and reduces conduction velocity
Effect of wavefront dispersion on the upstroke of the transmembrane action potential and the Na+ inward
current. A, inset: 2-dimensional strand of excitable tissue emerging into a large area.Action potential
upstrokes (A) and dVm/dt traces (B) show two components that are most prominent at the site of tissue
expansion (signals 6). C: time course of Na+ conductance, gNa. D: time course of Na+ inward current, INa.
Note that INa increases at the expansion site (site 6). [from Fast and Kléber.]
Wavefront Curvature
Effect of curvature on propagation. Left: stimulation of a perfused rabbit ventricular epicardial
layer with a single electrode (point stimulation from black dot) produces a convex excitation
front. Right: stimulation with a line of electrodes (line stimulation) produces an almost flat
excitation front. Numbers correspond to activation times in milliseconds. Isochrone lines are
shown at intervals of 3 ms. Average longitudinal velocity of curved wave is 13% slower than
that of flat wave. [from Knisley and Hill.]
Discontinuous Propagation
Propagation velocity depends on the repartition into subelements of low and high resistance. At high
discontinuity, conduction is only maintained within a certain range, characterized by a match between the
value of the low resistance elements, the number N of elements, and the value of R which separates them
Left: discontinuity is defined by a row of excitable elements (Rlow) separated by resistors (Rhigh).
Right: change of propagation velocity (q) vs. effective or overall longitudinal resistance (Ri)
plotted in the bottom panel is equal to the average longitudinal resistance.
Case A: continuous case, q2  1/Ri
Case B: moderate discontinuity, Rlow = 200/cm, Rhigh = 5,000  /cm
Case C: marked discontinuity, Rlow = 200, Rhigh = 10,000
[Modified from Joyner]
Safety Factor in Structurally Nonhomogeneous Tissue
A–D: conduction along a fiber with
inhomogeneous intercellular coupling.
A: starting from the junction between
cells 79 and 80, gap junction
conductance (gj) is increased from 0.08
to 2.5 µS.
B: action potentials (Vm)
C: safety factor (SF) along fiber (line
graph); local charge contributions from
INa (QNa) and ICa(L) (QCa) are shown in bar
graph.
D: peak values of INa (INa,max; solid line)
and ICa(L) [ICa(L),max; dashed line] along
fiber.
E–H: propagation across an expansion
site.
E: fiber expansion (branching) is
introduced at cell 80 and repeated twice
with an expansion ratio (ER) of 2.3
F: action potentials; numbers indicate
selected cells.G: line indicates SF along
fiber; bars indicate QNa and QCa. H:
INa,max (solid line) and ICa(L),max (dashed
line) along fiber.
[from Wang and Rudy].
Effects of Cell Size and Gap Junction Distribution
Effect of cell size and distribution pattern of gap junctions on cell-to-cell propagation delay (A)
and upstroke velocity of the action potential (B) during transverse propagation. Column a
represents values simulated from a model of the normal adult dog heart cell with gap junctions
located predominantly at the longitudinal ends. Column d represents values of the normal
neonatal rat heart cell with uniformly spaced gap junctions around the cell perimeter. Column b
corresponds to a virtual cell with the cell size of a dog myocyte and the gap junction pattern of
a neonatal rat heart cell; accordingly, column c corresponds to a virtual cell with the cell size of
a neonatal rat myocyte and the gap junction pattern of an adult dog myocyte. Note that cell size
has a significantly larger effect than gap junction pattern on both parameters. [from Spach et
al.]
Effects of Reduce Gap Junctional Conductance
AP upstrokes from the edge elements of
neighboring cells are shown in A and B (see
inset).
A: Normal gap junction conductance
B: Reduced coupling
For normal coupling (A), intercellular
conduction delay at the gap junction
(shaded) is approximately equal to
intracellular (myoplasmic) conduction time.
A 10-fold decrease in gap junction
conductance (B) increases the intercellular
delay and decreases intracellular conduction
time dramatically, resulting in gap junction
dominance of macroscopic conduction
velocity.
[Modified from Shaw and Rudy]
Subcellular Heterogeneity of Activation
Subcellular heterogeneity of activation (A), dV/dtmax (B), and INa (C) in a network of
simulated dog myocytes. Left graphs correspond to longitudinal propagation from left to
right, and right graphs correspond to transverse propagation from top to bottom. Note the
close direct correspondence between isochrone spacing and dV/dtmax and the inverse
correspondence to INa during both transverse and longitudinal propagation. Immediately
after passage of the wavefront through gap junctions, dV/dtmax and conduction velocity
show low values and INa is high (sites of current dispersion) while the inverse situation is
present before the passage of the waves through gap junctions (sites of partial collision).
Conscious rodent ECG recording device
Sliding head
cone
IP injection
opening
Adjustable end
gate
Sliding electrode
plate
Select regions without high
frequency noise
3
1.08810
1500
1000
500
0
yt
selft  1500
500
1000
1500
2000
3
 2.15510 2500
0
low
1
2
3
4
5
6
7
8
9
10
11
12
13
14
timet
Criteria for data analyses must be fine-tuned for each application
15
high
Mouse Raw Data Traces
Lead 1 ECG
Respiration
0
0.5
Time (secs)
1.0
Analysis of means of ECG signal
parameters
1000
817.4635
HR
P-wave
QRS
T-wave disp 
1
0
"R-R"
0
1
"Pon"
72
2
"Pmax"
86
3
"Pend"
106
4
"Qon"
194
5
"Qmax"
199
6
"Ron"
202
7
"R"
210
8
"S"
217
9
"J"
220.9216
10
"Tmax"
241
11
"Tend"
266
12
"a_Pon"
-14.0011
13 "a_Pmax"
39.2815
14 "a_Pend"
-38.6755
15
"a_Qon"
-59.344
16 "a_Qmax"
-91.5149
17
"a_Ron"
0.5488
18
"a_R"
817.4635
19
"a_S" -173.4002
20
"a_J"
0
21 "a_Tmax"
147.2388
22 "a_Tend"
8.2145
Amplitude
(measured units *1000)
0
800
600
m_sigt
400
ypo
200
0
 173.4002 200
0
0
20
40
60
80
tdt1000  ptodt1000
Time (ms)
100
120
140
140
Voltage-Sensitive Dye Imaging of Mouse Ventricle
A
B
RV
LV
Mouse ventricular
activation: Sinus
rhythm
Activation of Mouse Atria
Right atrium
Left atrium
Pacing site
LV
Apex
RV
LV
Apex
Activation Pattern in Sinus Rhythm
Rat
Human
Durrer et al, Circulation,
41:899-912, 1970
Motion Artifacts
Activation and Repolarization
in Acute Ischemia
• Coronary artery ligation  ischemic area
• Recording conditions:
– 2 mM Ca2+
– 3 M Cytochalasin-D for motion artifact
reduction
Ischemic zone
Ventricular Fibrillation