Restitution Curve Splitting As A Mechanism For The Bifurcation To Alternans

Restitution Curve Splitting
as a Mechanism
for the Bifurcation to Alternans
Elizabeth M. Cherry
Flavio H. Fenton
Cornell University
Alternans
Alternans is a beat-to-beat alternation in cellular
action potential shape and duration that leads to
alternans in the T-wave of the ECG.
Alternans can be electrical and/or mechanical; here we
focus on electrical.
Alternans often precedes
more dangerous arrhythmias
like ventricular fibrillation.
Wellens HJ. 1972. Chest 62, 319.
Raeder RA, et al. 1992. N Engl J Med 326, 271.
Alternans
At the cellular level, alternans appears as a beatto-beat long (L)-short (S) alternation despite a
constant pacing period (cycle length CL).
Action potential duration (APD) and/or amplitude
may alternate.
Alternans Bifurcation
Plotting APD as a function of
cycle length (period) shows a
period-doubling bifurcation.
At short cycle lengths, the
curve usually terminates when
every other beat is blocked.
Restitution Curve
Plotting APD as a function of preceding DI gives the
restitution curve, which provides a first approximation of
the systems dynamics.
Defining APDi+1=f(DIi)=f(CL-APDi) gives an iterative map
(for a fixed period CL=APDi+DIi).
Linearizing around the fixed point APD*=f(DI*) by letting
APDi=APD* + APDi gives APDi+1=-f(DI) APDi ,
which has a bifurcation when |f(DI)| = 1.
DI
APD
APD (ms)
APD Restitution
Restitution Curve
APDi+1=f(DIi) is stable when |
f(DIi)|<1.
Alternans is predicted for |
f(DIi)|<1.
APD (ms)
APD Restitution
pe
o
l
S
=1
JB Nolasco, RW Dahlen. 1968. J Appl Physiol 25, 191.

MR Guevara et al. 1984. Comput Cardiol, 167.
A Karma. 1993. Phys Rev Lett 71, 1103.
Cobwebbing technique useful for

visualization of the iterative map.
(Similar to logistic map.)
Restitution Curve
APDi+1=f(DIi) is stable when |
f(DIi)|<1.
Alternans is predicted for |
f(DIi)|<1.
APD (ms)
APD Restitution
pe
o
l
S
=1
JB Nolasco, RW Dahlen. 1968. J Appl Physiol 25, 191.

MR Guevara et al. 1984. Comput Cardiol, 167.
A Karma. 1993. Phys Rev Lett 71, 1103.
But in experiments,
alternans boxes slide
down and the
magnitude of
alternans is smaller.
APD (ms)
In models and onedimensional maps,

alternans is
characterized by
nested boxes and
large magnitude.
APD (ms)
Alternans Characteristics
DI (ms)
Period (ms)
Restitution Curve Splitting

Sliding boxes can be explained if the restitution curve
splits into two branches.
Each DI,APD pair then involves one point from each
branch.
Branches can have any slope, steep or flat.
Canine Purkinje fiber
Restitution Splitting in Experiments

Microelectrode recordings are used.
Decreasing temperature can increase alternans and
splitting.
Restitution Splitting in Experiments

During alternans,
lines with slope one
connect DI,APD
pairs.
Branch slopes can be
steep or flat.
Purkinje fibers more
likely to be steep;
epicardium and
endocardium more
likely to be flat.
Long branch can be
above or below
short branch.
Slope 1
STEEP
FLAT
FLAT
FLAT
Calcium in Experimental Alternans

Reducing extracellular Ca2+ (from ~2 mM to
62.5 M) removes splitting but also eliminates
alternans.
2-Dimensional Map Model
APD (ms)
APD (ms)
A 2-dimensional map model using both DI and

peak calcium to predict APD can reproduce
splitting: APDn+1 = f (DIn,Can+1).
Purkinje splitting data are well-matched.
CL (ms)
DI (ms)
Restitution Splitting in Models

Some models also exhibit restitution curve
splitting.
Branches for FMG model have slope > 1, for HR
model have slope < 0.5.
Fox JJ et al. 2002. Am J Physiol 282, H516. Hund T, Rudy Y. 2004. Circulation 110, 3168.
Cherry EM and Fenton FH. 2007. Am J Physiol 292, H43.
Enhancing Restitution Splitting
Exponent decreasing
In the FMG model, restitution

splitting can be enhanced by
decreasing the exponent in the
Jup term (0.5-2.0).
Summary
Restitution splitting occurs experimentally in
normal canine Purkinje fibers and ventricular
tissue.
Slope of restitution curve branches can be steep or
flat; no slope > 1 criterion for alternans.
Models, 2-d map also can exhibit splitting.
Acknowledgements: Robert F. Gilmour, Jr., NSF, NIH

Web site: http://thevirtualheart.org

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Restitution Curve Splitting

Wellens HJ. 1972. Chest 62, 319.

Raeder RA, et al. 1992. N Engl J Med 326, 271.

JB Nolasco, RW Dahlen. 1968. J Appl Physiol 25, 191.

Cobwebbing technique useful for

JB Nolasco, RW Dahlen. 1968. J Appl Physiol 25, 191.

In models and onedimensional maps,

Restitution Curve Splitting

Canine Purkinje fiber

Restitution Splitting in Experiments

Restitution Splitting in Experiments

Calcium in Experimental Alternans

2-Dimensional Map Model

A 2-dimensional map model using both DI and

Restitution Splitting in Models

Enhancing Restitution Splitting

In the FMG model, restitution

Acknowledgements: Robert F. Gilmour, Jr., NSF, NIH

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