Download Current status of monophasic action potential recording: theories

Cardiovascular Research 41 (1999) 25–40
Review
Current status of monophasic action potential recording: theories,
measurements and interpretations
Michael R. Franz*
Cardiology Divisions of the Veteran Affairs and Georgetown University Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA
Received 6 February 1998; accepted 19 August 1998
1. Introduction
artifacts. Last but not least, important differences between
unipolar and bipolar recordings of both MAPs and conventional electrograms will be discussed, as they pertain to the
fidelity and spatial resolution of these recordings.
Monophasic action potentials (MAPs) are extracellularly
recorded wave forms that, under optimal conditions, can
reproduce the repolarization time course of transmembrane
action potentials (TAPs) with high fidelity [1–3]. While
TAP recordings require the impalement of an individual
cardiac cell by a glass-microelectrode and therefore generally are limited to in vitro preparations, MAPs can be
recorded from the endocardium and epicardium of the in
situ beating heart, including that of human subjects. MAP
recordings therefore are suitable for studying the characteristics of local myocardial electrophysiology, especially
of repolarization, in the clinical setting. This has made
MAP recordings an important bridge between basic and
clinical electrophysiology in multiple areas of arrhythmia
research [4].
Despite the growing use of the MAP recording method,
there still is surprisingly little hard data on the exact
mechanism by which MAPs are created and recorded. New
methods for recording MAPs recently have been proposed,
and new theories and models have been suggested to
explain the mechanisms that underlie the genesis of the
MAP signal. There have been attempts to record MAPs
from sites within the myocardial wall, an effort spurred on
by the discovery that mid-myocardial cells (M-cells) have
different repolarization characteristics than either epicardial or endocardial cells [5], and these different characteristics have been found to be important for the development of torsade de pointes arrhythmias [6]. This article
attempts to review the available information on the MAP
genesis and its particular recording modes. It also highlights some important MAP quality criteria and guidelines
for correct interpretation of MAPs and how to avoid
The first MAP was recorded in 1882 by Burdon-Sanderson and Page [7] who placed one electrode on the intact
epicardial surface and the other on an injured site of a frog
heart, and thereby captured the phasic electrical changes of
the cardiac cycle on a charcoal-covered recording drum.
Burdon-Sanderson and Page produced this injury by
cutting into the myocardium, and termed these recordings
monophasic action currents (later to be replaced by
monophasic action potentials). Until then, electrodes
placed on intact heart tissue had been recording multiphasic deflections, similar to those recorded today in the
human electrophysiology laboratory by conventional electrode catheters; so the term monophasic was a logical
choice. It was believed for several decades that such
monophasic action potentials could only be produced by
traumatic tissue injury or cellular disruption. Methods such
as cutting, stabbing or burning of a myocardial site were
invented to produce monophasic ‘injury’ currents [8]. In
¨ [9] introduced the suction electrode for
1934, Schutz
experimental MAP recording. In 1969, Korsgren et al. [10]
used a suction electrode catheter in a patient and recorded,
for the first time, MAPs from the in situ ventricular
endocardium. This pioneering step subsequently was amplified by the work of Olsson and coworkers [11–13] who
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washington.va.gov
Time for primary review 26 days.
2. Brief history of MAP recording techniques
2.1. The ‘ injury’ method
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M.R. Franz / Cardiovascular Research 41 (1999) 25 – 40
refined the suction electrode technique and demonstrated
the value of MAP recording in exploring human cardiac
electrophysiology, mainly of the right atrium. Injury was
still deemed necessary and to do this ‘cautiously’ in the
human heart by suction technique required the use of
three-way stop cocks, bubble filters to prevent air emboli
and other precautions [13]. Because this technique was
cumbersome and raised patient safety concerns, the suction
electrode technique never gained wide acceptance in the
clinical electrophysiological laboratory (nor FDA approval).
2.2. The ‘ contact’ electrode method
The first nontraumatic method for recording MAPs was
published in 1935 by Jochim et al. [14]. These authors
demonstrated that MAPs can be obtained by simply
pressing an electrode against the epicardium of the toad
ventricle while another electrode merely touched the
nearby epicardium (Fig. 1). They also showed that the
MAP is positive with respect to zero if the pressure
electrode is the active electrode (connected to the positive
amplifier input). This important observation went largely
unnoticed for many years. However, their observation was
in both methodology and interpretation surprisingly similar
to the current principle of recording MAPs by contact
electrode.
The ‘contact electrode technique’ for clinical use was
developed between 1980 and 1983 by Franz et al. [15,16].
With the contact electrode technique, MAP recordings can
be obtained from the human endocardium or epicardium
without suction but rather by pressing a nonpolarizable
electrode gently against the endocardium or epicardium.
Catheters and probes for endocardial and epicardial MAP
recording were developed for clinical studies and for
experimental studies [17–19]. Fig. 2 shows the clinically
Fig. 2. Sketch of contact electrode catheter design for recording MAPs
from endocardium in patients or large animals. The most widely used
version (the MAP–pacing combination catheter), which includes smallsurface pacing electrodes located 2 mm proximal to the catheter tip in an
orthogonal position, is shown. MAP electrodes are made of high-grade
Ag–AgCl powder suspended in a special polymeric matrix. Pacing
electrodes are made of platinum–iridium. This catheter also incorporates
a bidirectional steering feature (not shown). Additional designs are
described in previous publications by Franz [4,27].
most widely used MAP catheter, which also incorporates
pacing electrodes. The ability to record MAPs by the
nontraumatic contact electrode technique refuted the previous contention that myocardial injury (or suction) is a
prerequisite for MAP recording. Besides being more
simple and clinically safe, the contact electrode method
provides MAP recordings that, due to lack of myocardial
injury, are stable over time. This allows the clinical
electrophysiologist to monitor MAPs over periods of
several hours from the same endocardial site to assess, for
instance, the effects of antiarrhythmic drugs or cycle length
changes on local myocardial repolarization [16,20].
2.3. Genesis of the MAP: old and new theories
Fig. 1. MAP recordings obtained by Jochim et al. in 1935 [14]. MAP
signals were generated by pressing an electrode against the epicardium of
a toad heart. When the positive electrode (labeled 1) was pressed against
the epicardium, a positive MAP was obtained (A). When the negative
electrode (labeled 2) was pressed against the epicardium, a negative MAP
was obtained (C). A biphasic electrogram was obtained when both
electrodes merely touched the epicardium (B).
The MAP is measured with an extracellular electrode
that has a diameter of 1 to 2 mm and therefore cannot enter
a single cardiac cell. This has given rise to much debate
about the genesis of the MAP. The early literature on MAP
measurements focussed on the central issue of whether the
MAP signal is recorded with the electrode in contact with
injured (depolarized) myocardium or with the electrode in
contact with uninjured (intact) myocardium. Hans
Schaefer, a vehement protagonist of the former assumption, argued that MAPs can only be obtained when injury
is present and therefore the electrode in contact with
M.R. Franz / Cardiovascular Research 41 (1999) 25 – 40
injured muscle must be the different electrode [21,22].
Others countered that injured cells are electrically inactive
and therefore the electromotive force producing the MAP
must originate from the uninjured cells [23–25]. As will be
explained later, the truth appears to lie in the middle.
¨
2.4. The ‘ Schutz-hypothesis
’ on injury potentials
¨ in 1934–
Based on experiments in frog hearts, Schutz
1936 [8,9] promoted the theory that the MAP is the voltage
drop that is recorded between the different electrode (in
contact with injured myocardium) and the indifferent
electrode (in contact with uninjured myocardium). He
assumed leak current flow between the injured cells and
the uninjured myocardium and explained the MAP by the
following simple equation:
Einj 5 Em 3 (R e 1 R i ) /R i
where Einj is the MAP voltage, Em is the transmembrane
voltage, R e is the extracellular resistance and R i is the
intercellular resistance. This hypothesis assumes that the
MAP is the result of a voltage source, with all electromotive generators in parallel. An increase in extracellular
resistance (for instance, by drying the heart’s surface)
would result in a greater MAP amplitude (which in fact
occurred), and a decrease in extracellular resistance, by
wetting the heart’s surface with electrolyte solution, would
decrease the MAP amplitude (which also is true for injury
potentials in this setting). This hypothesis also assumes
that short-circuiting between the injured cells and the
extracellular space is minimized by using a tight electrical
seal between the MAP recording electrode and the surrounding tissue. The suction electrode method was promoted to some extent because it was believed to provide
such a seal. This theory has some semblance to the
sucrose-gap technique that is used to record the TAP in
vitro without transmembrane impalement [26].
2.5. The ‘ volume conductor’ hypothesis
Based on the following observations, Franz [27] con¨ hypothesis does not apply to the
cluded that the Schutz
contact electrode method but that the contact electrode
MAP results from a current source and is governed by
volume conductor theory. (1) The contact electrode obtains
MAPs from the endocardium while surrounded by the
blood pool in the ventricular or atrial cavity and has no
surrounding seal, suggesting that the extracellular resistance has no influence on the amplitude of the MAP. This
was confirmed by experimental studies in small animal
hearts [27]. (2) The number of cells (single electromotive
generators) contributing to the MAP seems important
because greater contact pressure between the tip electrode
27
and myocardium increases the MAP amplitude [16].
Furthermore, MAPs of greater amplitude are recorded
from ventricular myocardium than atrial myocardium or
from larger hearts (e.g. canine and human hearts) as
compared to small hearts (e.g. rabbits), suggesting that wall
thickness beneath the MAP tip electrode plays a role in
determining the MAP amplitude [27]. This suggests that
the MAP amplitude is related to the volume of cells that
contribute to the MAP genesis and that the MAP signal
results from a current source, with individual electromotive
generators more or less in series.
2.6. MAP genesis by the contact electrode method
Fig. 3 schematically depicts the hypothesis by which
the contact electrode method produces and records MAPs.
Pressure exerted focally against the myocardium depolarizes the group of cells subjacent to the electrode to a level
that is estimated at 230 to 220 mV with respect to the
diastolic extracellular reference potential. Because sodium
channels remain inactivated at these voltage levels, these
cells are unexcitable and thus unable to participate in the
periodic depolarizations and repolarizations that occur in
the adjacent (normal) myocardium. The group of cells
depolarized by the contact electrode provide a ‘frozen’
potential, which contrasts with the time-varying potential
in the unaffected adjacent cells. Assuming preserved
electrical coupling, this causes a time-varying electrical
gradient between the depolarized (inexcitable) cells subjacent to the electrode and the adjacent (excitable) cells. This
electrical gradient produces current flow across the boundary between these two states. During electrical diastole,
this gradient results in a source current emerging from the
normal cells and a sink current descending into the
depolarized cells subjacent to the MAP electrode. The sink
current produces a negative electrical field that is proportional to the strength of current flow, which depends on the
potential gradient and the number of cells that contribute to
the interface between the subjacent depolarized and the
adjacent nondepolarized cells. During electrical systole, the
normal cells adjacent to the MAP electrode undergo
complete depolarization, which overshoots the zero potential by some 30 mV, whereas the already depolarized
and therefore refractory cells subjacent to the MAP
electrode cannot further depolarize and maintain their
potential at the former reference level. As a result, the
former current sink reverses to a current source, producing
an electrical field of opposite polarity. According to this
hypothesis, the MAP recording reflects the voltage time
course of the normal cells that bound the surface of the
volume of cells depolarized by the contact pressure. Thus,
both the depolarized (‘electrically frozen’) cells and the
active cells of the neighboring myocardium contribute to
the genesis of the boundary current that produces the MAP
field potential; one cannot exist without the other.
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M.R. Franz / Cardiovascular Research 41 (1999) 25 – 40
Fig. 3. Diagram illustrating the hypothesis underlying the genesis of MAP recording by contact electrode. (A) Late electrical diastole. The myocardial cells
are 290 mV negative inside with respect to the outside. The pressure of the tip electrode (black ellipsoid) against the myocardium results in constant
depolarization of the subjacent cell volume (shaded hemisphere). A fixed depolarization to 220 mV is assumed but could be slightly larger or smaller. The
potential gradient across the boundary between the normal diastolic potential and the fixed depolarization underneath the contact electrode creates current
flow (circular lines), which, in the extracellular space, flows from normal to depolarized tissue. Under the present volume conductor conditions, this creates
a current sink and a corresponding sink potential at the contact electrode site. The MAP recording (inside in upper right) shows a steady potential negative
to zero. An arriving action potential wave, which carries an inside potential of 130 mV near the upstroke, is shown to the right of the contact electrode site.
(B) Early electrical systole. The action potential wave arrives at the contact electrode site. The cell volume depolarized by the contact pressure is
unexcitable and maintains its potential at 220 mV. Its initial 130 mV inside brings to the contact site a relative positive inside charge and a relative
negative outside charge. This leads to a reversal of the boundary current and field potential polarity. The MAP now moves in the positive direction and
inscribes an upstroke and early phase 1. (C) Mid electrical systole. The propagating action potential wave has completely encompassed the MAP recording
site. As the TAP wave gradually repolarizes, the boundary gradients gradually diminish. The MAP undergoes slow repolarization, which nears the
isoelectric line as the TAP potential approaches the potential in the pressure-depolarized cell volume. (D) End electrical diastole. The propagating TAP
wave recedes from the MAP electrode contact site. Voltage gradients return to their pre-existing (diastolic) state. The cycle is completed and results in a
MAP recording that faithfully resembles the original TAP recording. Abbreviations: MAP5monophasic action potential recorded from extracellular space.
TAP5transmembrane action potential recorded from intracellular space.
3. Different versus indifferent electrode: which is
which and which one records the MAP?
Based on the above model and experimental observations, it has become evident that the MAP originates from
cells in the immediate vicinity of the electrode that causes
persistent depolarization. It is also evident that, to obtain
an upright MAP signal, the MAP-exploring electrode must
be connected to the positive input of the amplifier and the
reference electrode to the negative input. The following
data help to elucidate further the relationship between the
active (different) and inactive (indifferent) electrode.
3.1. Unipolar MAP recordings
The name ‘monophasic action potentials’ (MAPs) was
introduced at the time of its first discovery in 1882 [7].
Before, only biphasic or multiphasic electrograms had
been recorded from the surface of the heart. Later, it
became obvious that extracellular monophasic action potentials can only be obtained by using a unipolar recording
method. To better understand the conditions giving rise to
monophasic action potentials, the following factors need to
be emphasized: If both electrodes are placed on intact
myocardium, a bipolar signal is obtained. If both electrodes are placed on injured or otherwise depolarized
muscle, the monophasic portion of the signal will be
canceled out. If one electrode is in contact with depolarized muscle and the other with active tissue, a monophasic
signal is recorded. By coupling the active MAP-exploring
electrode with a remote electrode, such as a ‘Wilson
central terminal’, a monophasic potential is still obtained
but will also contain far-field potentials. The extent to
which these far-field potentials contribute to the local MAP
signal is often unpredictable. If an area of myocardial
depolarization caused by ischemia or other causes exists
remote from the MAP recording site, the field potential
created across its boundaries may contaminate the local
M.R. Franz / Cardiovascular Research 41 (1999) 25 – 40
29
MAP signal to a greater or lesser extent, depending on the
particular geometry of the current sources with respect to
the position of the two MAP electrodes. This problem is
reminiscent of difficulties encountered in interpreting
precordial ST segment elevations or depressions when
more than one ventricular wall segment is injured by
ischemia [28]. Reciprocal changes, cancellations and expansions all may occur, making the precise localization of
the primary injury difficult.
3.2. ‘ Close-bipolar’ MAP recordings
The problem of MAP contamination by far-field potentials was recognized by Olsson [13], who advocated a
‘close-bipolar’ MAP recording approach. The electrical
field potential that is caused by applying suction or contact
pressure to the myocardium and that creates the MAP
seems to be confined to a finite region that does not extend
much beyond the area of depolarization. An electrode
placed 5 mm proximal to the depolarizing tip electrode
usually is far enough away from the MAP-generating
current and therefore can be used as a reference electrode
that is indifferent to the monophasic field. This closebipolar electrode arrangement provides a very small solid
angle towards more remote electrical forces and, by using
differential amplification, greatly reduces far-field potentials. It is this close-bipolar technique that makes the MAP
recording truly local, as the following two examples
illustrate:
1. Fig. 4 compares a unipolar MAP, a close-bipolar MAP
and a unipolar electrogram, all recorded with the same
catheter at the same location, during normal and ectopic
ventricular activation. The unipolar MAP shows major
differences in morphology during ectopic activation,
while the close-bipolar MAP does not. This underscores
the fact that, using the close-bipolar technique, the
MAP measures only local depolarization and repolarization events. These three signals were recorded by
three independent, high-impedance, differential amplifiers. Any two of the three recordings are the sum of
the third (similar to the three Einthoven leads). (Further
details in the legend to Fig. 4).
2. Fig. 5 shows three types of recordings obtained simultaneously from the anterior left ventricular (LV) epicardium of the in-situ canine heart: the close-bipolar
MAP, the unipolar MAP and the unipolar electrogram.
Occlusion of the LAD resulted in a decrease in the
amplitude of the close-bipolar MAP and a concomitant
increase in the ST segment of the unipolar electrogram,
with both changes being nearly reciprocal to each other.
The unipolar MAP, however, remained almost unchanged. Therefore, it must be concluded that unipolar
MAP recordings are not a reliable measure of local
electrical activity but are sensitive to influences originating from potential gradients at distant sites. Only close-
Fig. 4. (A) Diagram of a three-channel recording of close-bipolar MAP,
unipolar MAP and unipolar electrogram (EGM). (B) Comparison of
unipolar and close-bipolar MAP recording during beats of varying
ventricular activation sequence. The unipolar MAP shows significant
distortions in its waveform and duration while the close-bipolar MAP
retains essentially the same morphology with changes in duration due to
cycle length changes. The lowest tracing shows the unipolar electrogram
(EGM) that was recorded from the proximal MAP electrode against the
remote reference. It appears that the unipolar MAP is a hybrid between
the close-bipolar MAP and the unipolar EGM. All three recordings were
obtained from the same catheter located at the RV outflow tract.
M.R. Franz / Cardiovascular Research 41 (1999) 25 – 40
30
Fig. 5. Comparison of the effects of regional myocardial ischemia
(produced by occlusion of the left anterior descending (LAD) coronary
artery) on the close-bipolar and unipolar MAP and unipolar EGM. The
three recordings were obtained simultaneously from the epicardium of the
LAD region using the circuit arrangement shown in Figure 4A. Acute
ischemia resulted in a substantial decrease in the amplitude of the
close-bipolar MAP recording. The unipolar EGM showed prominent ST
segment elevation. The unipolar MAP recording, in contrast to the
close-bipolar MAP recording, showed little change.
bipolar MAP recordings reflect the local electrophysiological changes during regional ischemia.
3.3. Field of view of MAP recordings
Even with the close-bipolar MAP recording technique,
which ascertains that the MAP recording reflects local
electrical activity at the recording site, the actual spatial
resolution of the MAP has not been determined with
accuracy. Levine et al. [29] addressed this issue by
analyzing the ‘foot’ of MAP signals recorded from slices
of canine myocardium and found that approaching electrical activity may be seen from areas as far as 10 mm from
the MAP tip electrode. However, these recordings were
done from a tissue preparation that was not perfused but
only superfused, and only a unipolar recording technique
was applied. Therefore, the foot of the MAP likely
included far-field electrical activity.
One obvious determinant for the field of view is the size
of the MAP tip electrode that produces and explores the
boundary currents between the depolarized cells and
adjacent normal cells (see above). The spatial resolution
cannot be less than the tip electrode diameter (typically 1
to 2 mm). Another determinant is the distance and the solid
angle between the tip electrode and the reference electrode
with respect to the MAP voltage field source. With our
method, the interelectrode distance is commonly 5 mm.
When the tip electrode is kept in an ideal position
perpendicular to the myocardial surface, the solid angle
with respect to areas lateral to the tip electrode is very
small, resulting in effective cancellation of remote electromotive sources if differential amplification is used.
Franz et al. [2] impaled myocardial cells with microelectrodes in the immediate vicinity of the contact site of the
MAP electrode and measured normal transmembrane
resting and action potentials as close as 0.1 mm to the
MAP tip electrode circumference, suggesting that the area
of depolarized tissue which constitutes the MAP boundary
is confined to the MAP electrode size. These authors also
recorded MAPs across a sharp transmural infarct border
and noted an abrupt transition from normal to ischemic
MAP signals within less than 5 mm of the ischemic border
[17]. This further supports the view that the MAP signal
reflects electrical activity from a very small area, not less
than the electrode size and probably not more than 5 mm
in diameter. The ‘depth of view’ with which the MAP
electrode senses the electrical activity of myocardial tissue
beneath the MAP contact electrode has not yet been
determined. The fact that MAP recordings from thicker
wall segments (left ventricle, large animals) have substantially greater amplitudes than recordings from thin-walled
tissue (right atrium, small animals) suggests that tissue at
some considerable depth beneath the exploring electrode
contributes to the genesis of the MAP signal [27].
4. How accurate are MAP recordings compared to
transmembrane action potentials?
The accuracy with which MAP recordings reflect the
local cellular depolarization and repolarization was examined in several studies that compared the MAP with the
simultaneously recorded transmembrane action potential
(TAP) [1–3]. These studies have pointed out a number of
similarities and dissimilarities between the MAP and TAP.
In general, high-quality MAP recordings should satisfy the
criteria listed in Table 1.
Table 1
MAP quality criteria
1. MAP amplitude (baseline to plateau crest) not less than 10 mV
2. Fast, clean upstroke (rise time not longer than 5 ms)
3. No major contamination by intrinsic deflection or QRS
4. Smooth, upwardly convex plateau
5. Horizontal diastolic baseline [no undershoot (‘dip’) during early mechanical diastole, and no upsloping potential for the remainder of diastole]
6. MAP wave forms closely similar during normal and ectopic activation sequence
M.R. Franz / Cardiovascular Research 41 (1999) 25 – 40
4.1. MAP amplitude and resting potential
Both the diastolic and action potential amplitude are
markedly less in the MAP as compared to the TAP. The
amplitude of the contact electrode MAP typically ranges
between 5 and 50 mV, although values as high as 81 mV
have been reported [27]. Despite this variability, which
depends on the contact pressure and tissue type (see
above), relative changes in the MAP resting and action
potential amplitude can be interpreted as long as a stable
baseline recording is obtained before and after the intervention [17,30].
4.2. Repolarization time course
The MAP faithfully reflects the duration as well as the
configuration of the repolarization phases one through
three of the TAP [2,31]. Fig. 6 shows TAP and MAP
recordings obtained simultaneously from closely adjacent
31
sites in an isolated perfused rabbit septum preparation
during interventions that influence the action potential
duration and configuration [31]. Each panel shows TAP
and MAP signals superimposed onto each other after they
have been rescaled to match in amplitude. With each of the
interventions shown, changes in the shape and duration
were nearly identical in the TAP and MAP recordings.
4.3. Upstroke velocity
The maximum upstroke velocity (Vmax ) of the MAP is
much smaller than that measured with an intracellular
electrode. In the canine heart, Vmax of the ventricular MAP
averages 7 V/ s [17], compared to 200 to 300 V/ s in the
transmembrane record [32]. The smaller rise in velocity of
the MAP is in part due to its smaller amplitude and in part
to the fact that the MAP electrode records the electrical
activity from a group of cells whose depolarizations occur
sequentially with time. Despite the marked difference in
absolute magnitude of Vmax between TAP and MAP
recordings, relative changes in Vmax may provide important
information. Franz et al. [17] demonstrated during acute
ischemia that Vmax of the MAP decreased by 95% at only 5
min of coronary artery occlusion. This makes the MAP
upstroke velocity a highly sensitive marker of myocardial
ischemia. Under stable recording conditions, MAPs also
provide reliable measures of drug-induced changes in Vmax ,
which can help classify use-dependent properties of sodium channel-blocking drugs [30].
4.4. Upstroke and phase 1 morphology
Fig. 6. Comparison of monophasic (MAP) and transmembrane (TAP)
action potential recorded simultaneously from closely adjacent sites in a
rabbit isolated perfused intraventricular septum (IVS) preparation. In
panel A, the rate of pacing was increased from 1.25 to 2.5 Hz, resulting in
significant shortening of the action potential duration. The recordings in
panel B show the effect of replacing the normal perfusing and bathing
solution with a calcium-free solution. With the pacing rate maintained at 1
Hz, the action potential greatly increases in plateau duration, resulting in
a more rectangular configuration. In panel C, the effects of an extrasystole
and a subsequent pause on action potential duration are shown. With all of
these interventions, changes in the shape and duration were nearly
identical in the TAP and MAP recordings. From Franz et al. [31].
Using high band-width amplification, the upstroke of the
MAP contains a rapid deflection, appearing as a biphasic
notch within the MAP upstroke or a spike overshooting or
undershooting it [2,16]. This notch is the remnant of the
‘intrinsic deflection’ seen in the myocardial surface electrogram prior to applying contact pressure and the development of the MAP. This intrinsic deflection may appear as a
positive spike immediately preceding the MAP plateau
phase, mimicking an ‘overshoot potential’ or ‘phase 1
repolarization’. This, however, should not be taken as
evidence that the MAP reflects recordings from specialized
conductive tissue or represents predominant KIto channel
activity of epicardial myocardium, as suggested by some
investigators [33]. As Fig. 4 shows, during excitations
originating from different ectopic ventricular sites, with
their attending alterations in activation sequence, the
upstroke phase alters its shape and overshoot potential
despite the fact that the MAP electrode remains at a
constant location.
There currently is no reliable method to eliminate the
intrinsic deflection which, in contrast to the remote QRS,
originates from myocardium very near the exploring MAP
tip electrode. For this reason, we define the MAP amplitude as the distance from the baseline to the crest of its
32
M.R. Franz / Cardiovascular Research 41 (1999) 25 – 40
plateau phase, and not to the peak of the upstroke. It also
underscores why the rise velocity of the MAP upstroke
cannot be equated with that of the transmembrane action
potential.
4.5. Afterdepolarizations
Basic electrophysiologic studies have provided strong
evidence that afterdepolarizations play a significant role in
the genesis of triggered arrhythmias, such as torsade de
pointes. These afterdepolarizations, which can be distinguished between early (EADs) and delayed (DADs) afterdepolarizations, cannot be detected by conventional intracardiac recordings. MAP recordings have been used to
detect EADs or DADs during experimental [34–39] and
clinical [40–44] electrophysiologic studies and relate them
to triggered arrhythmias. However, it is extremely important to apply stringent quality criteria to the MAP
recording before interpreting abnormalities in the final
repolarization time course as EADs or DADs. ‘Humps’
and ‘wobbles’ in the MAP recording simply may be the
result of unstable electrode contact (see Section 5). The
following criteria may be helpful in distinguishing true
EADs or DADs from movement artifacts: (1) Experimental conditions usually allow the investigator to obtain
baseline recordings before beginning interventions. These
baseline recordings should be stable with a smooth phase
three and a horizontal phase four without appreciable
deviations. (2) EADs, when they occur in response to
interventions such as application of catecholamines or
action potential duration (APD)-prolonging drugs, or shortlong pacing sequences, should be critically evaluated to
determine if they bear sufficient morphological resemblance, and behavior compliant with, data known from
transmembrane recordings. (3) Washout of the inducing
agent or cessation of the interventional pacing protocol
should result in the disappearance of EADs and return to
baseline MAP tracings. Even then, no absolute proof of the
validity of the EADs or DADs is obtained. There will
always be a degree of uncertainty, which diminishes
proportionally with the experience of the investigator and
his / her ability to suppress bias. This author believes, after
careful inspection of the experimental protocols and figures, that the work presented in references [34–44] is
convincing and supports the usefulness of MAP recordings
for the purpose of identifying EADs or DADs under the
given experimental conditions.
ing of the catheter tip electrode permits precise tracking of
the wall motion, the rhythmic dilatation and contraction of
the ventricle will alternatingly lessen and increase the
contact pressure. This may result in transient amplitude
changes of the MAP signal. These transient potential
changes take a positive or negative direction depending on
the time of pressure change with respect to the phase of the
MAP signal. Diastolic dilatation of the ventricle may cause
a decrease in contact pressure, resulting in a decrease in
diastolic MAP amplitude. Because the diastolic phase of
the MAP is negative with respect to zero potential, a
decrease in diastolic MAP amplitude may be misinterpreted as ‘spontaneous diastolic depolarization’ or ‘DADs’.
Conversely, systolic contraction of the ventricle may
increase the contact pressure between the catheter tip and
the endocardium, resulting in a transient increase in MAP
amplitude. Because the systolic phase of the MAP is
positive with respect to zero potential, an increase in
systolic MAP amplitude may cause an elevation of the
later part of the MAP or produce false ‘EADs’. An
example of a MAP tracing presumably distorted by the
above-described contact pressure changes is shown in Fig.
7. Compared to the correct waveform (broken line), the
MAP shows a rapidly upward-sloping potential during
diastole. This is most likely due to loss of endocardial
electrode contact during diastolic relaxation (outward
motion) of the ventricular wall. These movement artifacts
can be minimized by using highly elastic catheters and
careful positioning, which allows the distal catheter shaft
to flex back and forth during the ventricular contraction
and relaxation process, thereby maintaining steady contact
pressure.
5.1. Mechanoelectrical feedback
The issue of motion artifacts is further complicated by
the fact that nonuniform ventricular contraction and relaxation can produce true electrophysiologic changes. A yet
little understood phenomenon, known as contraction–exci-
5. Movement artifacts
One of the most important limitations of MAP recordings is that they may be distorted by motion artifacts
caused by the beating heart. The MAP amplitude is (within
limits) proportional to the contact pressure exerted by the
electrode against the myocardium. Unless correct position-
Fig. 7. Artifacts in the MAP recording (solid line) due to unstable contact
between the catheter tip electrode and the endocardium. Dotted line
shows stable recording. See text for discussion.
M.R. Franz / Cardiovascular Research 41 (1999) 25 – 40
33
Fig. 8. MAP changes caused by abrupt myocardial stretch. Stretch pulses applied to the left ventricle of the isolated rabbit heart via a servo-driven
fluid-filled balloon caused transient depolarizations which, when reaching threshold, triggered propagated excitations. LV2–EPI5MAP recording from
epicardial site of left ventricle. DVOL5left ventricular volume changes. From Franz et al. [49].
tation coupling [45] or mechanoelectrical feedback [46],
can lead to changes in action potential duration [47–49],
‘afterdepolarizations’ [50–52] and even arrhythmias [53]
(Fig. 8). The mechanism underlying these electrophysiologic effects is believed to be myocardial stretch
[54]. Nonuniformity of ventricular contraction and relaxation [55] creates conditions where some wall segments
undergo excessive lengthening during diastole or even late
systole, causing regional heterogeneity of load-induced
electrophysiologic changes. Some investigators have discarded afterdepolarizations in MAP recordings categorically as movement artifacts because they did not observe the
same afterdepolarizations in intracellular microelectrode
recordings [56]. However, to ensure stable microelectrode
impalements, intracellular recordings are usually obtained
from excised, mechanically relatively quiescent, preparations that do not experience physiologic load or length
changes. Thus, validation of the MAP by comparing it
against the ‘gold standard’ of the transmembrane action
potential must fail in this respect. This makes the reliable
distinction between ‘true’ and ‘false’ motion-induced MAP
changes one of the greatest challenges of the MAP method.
repolarization levels [58,59]. However, due to the complexity of the MAP signal, interactive programs and
validation by manual observers are recommended [58].
7. Simultaneous measurement of MAP duration and
refractory period at the same site
Conventional electrode catheters used in electrophysiologic studies allow determination of the effective
refractory period (ERP) at a given endocardial site but
cannot elucidate the relationship between the action potential duration and the ERP. The currently used version of
the contact electrode catheter provides both pacing and
MAP recording capabilities with a single catheter, thereby
allowing easy and accurate measurements of both the ERP
and APD simultaneously and at the same site in the human
heart [60]. Unlike conventional quadrupolar electrode
catheters, the pacing electrodes in this MAP recording–
pacing combination catheter are oriented orthogonally
halfway between the distal (exploring) and proximal
6. Measurement and analysis of MAP recordings
6.1. Determining the MAP duration
Because the asymptotic end of repolarization makes
precise measurement of total MAP duration difficult, the
MAP duration is usually determined at a repolarization
level of 90% (or another fraction) with respect to the MAP
amplitude. The MAP amplitude is being defined as the
distance from the baseline to the crest of the MAP plateau,
not its upstroke peak (Fig. 9) [16]. Others have suggested
using the intersection between the diastolic baseline and a
tangent placed on phase three repolarization [57], although
this may produce more arbitrary results, depending on the
slope of final repolarization. We define the beginning of the
MAP as the instance of fasted rise time of the MAP
upstroke or, if detectable, the notch of the intrinsic
deflection, which is superimposed onto the MAP upstroke
[16]. Computer algorithms have been developed to automate the analysis of MAP duration at user-specifiable
Fig. 9. Method of analysis of the MAP signal. The amplitude of the MAP
is measured as the distance from the diastolic baseline to the crest of the
MAP plateau phase, not the peak of the upstroke. The duration of the
MAP signal is measured as the interval, along a line horizontal to the
diastolic baseline, from the fasted part of the MAP upstroke (or the
intrinsic deflection, if discernible) to the desired repolarization level. The
example shows evaluation of MAP duration at 30, 60 and 90% repolarization. From Franz [16].
34
M.R. Franz / Cardiovascular Research 41 (1999) 25 – 40
(reference) MAP electrode (Fig. 2). This electrode configuration provides for extremely low capture thresholds
(0.02–0.25 mA, mean 0.09 mA), reducing the interference
between the pacing artifact and the MAP signal to a
minimum [60]. Pacing artifacts are negligibly small and
sometimes hardly discernible despite the fact that the
pacing electrodes are very close to the MAP recording
electrodes (Fig. 10).
Several factors likely account for the unusually low
capture threshold and minimal stimulus artifacts. First, the
pacing electrodes used in this catheter have a smaller
surface area than conventional ring electrodes and thus
produce higher current densities. Second, the electrical
field produced by the pacing current is positioned horizontally above the vertical field that produces the MAP, with
subsequently less contamination of the latter. Third, the
MAP catheter provides and ensures close and stable
contact with the endocardium (unstable contact would
result in no or unstable MAPs). Fourth, and perhaps most
important, only the tip (MAP) electrode is in contact with
depolarized myocardium, while the stimulus electrodes
usually do not exert pressure against the endocardium.
This prevents the pacing site from being depolarized and
made relatively more refractory.
Fig. 10 demonstrates how the effective refractory period
(ERP) is determined simultaneously with the concomitant
MAP duration. In normal ventricular myocardium and in
the absence of sodium channel-blocking drugs, the relationship between the MAP duration and the ERP in the
Fig. 10. Simultaneous determination of action potential duration at 90%
repolarization (APD90) and effective refractory period (ERP) in vivo
using the MAP pacing / recording combination catheter. S1 and S2 denote
the basic and the extra stimulus artifacts. The upper tracing shows the
shortest S1–S2 coupling interval that elicits a propagated response. The
lower tracing shows failure to capture at a 5-ms shorter coupling interval.
S1-stimulus artifacts are partially superimposed on the MAP upstroke but
do not interfere with the ability to analyze the onset and duration of the
MAP signal. S2-stimulus artifacts are superimposed on the repolarization
phase but do not distort its time course. From Franz et al. [58].
canine [19,60] and human [61] heart has been shown to be
constant and independent of heart rate. Antiarrhythmic
drugs with sodium channel-blocking properties often
produce greater increases in refractoriness than in action
potential duration; this drug-induced post-repolarization
refractoriness progresses with increases in stimulation
frequency [62–64]. Simultaneous determinations of MAP
durations and ERP therefore are useful in verifying the
electrophysiologic profile of antiarrhythmic drugs predicted from in vitro studies for the human heart and may
aid in our understanding of the antiarrhythmic mechanisms
of such drug effects.
8. Are intramural MAP recordings possible?
The impetus for recording MAPs intramurally came
from the desire to record disparities of the APD across the
myocardial wall of the intact heart because it has been
shown by microelectrode techniques that such disparity
exists and that mid-myocardial cells (M-cells) have longer
APDs and are more prone to exhibit EADs at slow rates
than epicardial or endocardial cells [65,66]. Thus, the
recording of truly local intramyocardial MAP recordings
would advance the understanding of the mechanism of
many arrhythmias, most notably of the ‘torsade de pointes’
variety. Attempts have been made to obtain MAPs intramyocardially by inserting a multipolar plunge electrode
into the myocardial wall and coupling it with a reference
electrode placed on a remote (epicardial) site of the
ventricle [67]. The initial injury potential resulting from
inserting the plunge electrodes into the myocardial wall
was allowed to subside until a normal electrogram was
obtained. The remote electrode site was then depolarized
by KCl. This led to a new monophasic recording. This
MAP was of reversed polarity when connected to the
amplifier in the conventional manner (see above). To make
this MAP upright, the exploring (intramural) electrode was
coupled to the negative amplifier input and the KCl
electrode to the positive amplifier input. As discussed
earlier, this suggests that the monophasic portion of the
recording derives from the remote (KCl) electrode and not
from the intramural plunge electrode. Because of the wide
spacing between the intramyocardial electrode and the
remote KCl electrode, these ‘intramural MAP recordings’
by definition represent largely unipolar MAP recordings
that are subject to contamination by far-field potentials in
much the same way as unipolar electrograms. Superimposition of disparate T wave durations on these MAPs
may give the impression that MAPs of different duration
are recorded from different intramural sites. Such recordings, while to some degree reflecting intramural differences, are not truly local as obtained by the close-bipolar
technique but hybrids of local and far-field potentials.
M.R. Franz / Cardiovascular Research 41 (1999) 25 – 40
8.1. Are chronic MAP recordings possible?
Permanent monitoring of local activation and repolarization characteristics would be very desirable. This, if
combined with an implantable telemetry device, could be
used to monitor the effects of antiarrhythmic drugs on
myocardial repolarization at specific intervals, or related to
the onset of proarrhythmic events. Progression of cardiomyopathy and heart transplant rejection are other fields
that would benefit from continuously available MAP
interrogation. As understanding of the cellular basis of
arrhythmias grows, abnormal changes of MAP signals
recorded by permanent electrodes and transmitted by
telemetry may become predictors and warning signals of
life-threatening arrhythmic events.
Unfortunately, this does not seem possible with currently available MAP methods. MAPs have a tendency to
decrease their amplitude and change their morphology over
time. The MAP signal deterioration is much more rapid
(minutes) with techniques that create MAPs by frank
cellular injury, such as suction or stabbing the tissue with a
needle or plunge electrode. It is gradual (several hours)
with the contact electrode, especially when only moderate
contact pressure is applied. The loss in MAP amplitude
over time is associated with two important features. One is
that, as the MAP amplitude decreases, the initial spike
becomes more prominent. This spike is the remnant of the
intrinsic deflection (which becomes unmasked as the MAP
plateau amplitude decreases) and should not be confused
with a ‘spike-and-dome’ configuration of TAPs, as was
done by Tande et al. [33]. The second feature that
accompanies the decrease in the MAP amplitude is that the
loss in total (plateau) amplitude is primarily due to a
decrease in the diastolic voltage of the MAP. The mechanisms underlying the amplitude decrease of injury potentials was studied extensively by De Mello [68], who
concluded that it is promoted by cellular uncoupling
between the injured and normal cells. Several experiments
led De Mello to believe that this electrical uncoupling
takes place at the site of gap junctions and that calcium
Table 2
Clinical applications of monophasic action potential recordings
Effects of rate and rhythm on action potential duration (APD)
Afterdepolarizations and polymorphous ventricular tachycardias
— Congenital or acquired long QT syndromes
— Other forms of triggered arrhythmias (right ventricular outflow tract VT?)
Effects of antiarrhythmic drugs on APD
Effects of antiarrhythmic drugs on ERP/APD ratio
Evaluation of T-wave changes and mechanism of T-wave alternans
Measurement of dispersion of repolarization
Myocardial ischemia detection and infarct mapping
— Distinction of viable vs. nonviable myocardium
Monitoring of radiofrequency catheter ablation
35
and proton ion accumulation at these sites plays a pivotal
role [69–71].
9. New avenues for MAP recordings
An overview of past and future clinical uses of the MAP
technique is given in Table 2. Besides a large number of
clinical applications already published, there are newer
uses for the MAP recording technique currently undergoing experimental evaluation and clinical validation.
9.1. MAP recordings as a measure of myocardial
viability
Mechanical performance of heart muscle decreases very
rapidly following coronary artery occlusion and may
remain ‘stunned’ or ‘hibernating’ and, despite surviving
myocardium being present, may require prolonged periods
of time for full recovery. Electrical activity may still be
preserved due to a lesser metabolic demand for maintaining membrane potential than for the upkeep of mechanical
work. Measurements of mechanical activity by echocardiographic or angiographic means may not be able to
distinguish between stunned or hibernating (yet still viable)
myocardium and myocardium that is jeopardized beyond
salvage. This is a potential important application of the
MAP recording technique.
It follows from the explanation of the genesis of the
MAP (see above) that MAPs can be created only when the
electrode is impinging on viable myocardium. In contrast,
when the electrode is pushed against nonviable tissue, e.g.
a myocardial scar, local depolarization cannot occur and
the recording is largely isoelectric [16]. Following coronary artery occlusion, changes in the MAP recording
track the progression of myocardial ischemia by exhibiting
amplitude and morphology changes [17,72] similar to
transmembrane action potentials [73]. Within minutes, the
MAP shows a decrease in amplitude and duration, especially of the plateau phase, and a decrease in upstroke
36
M.R. Franz / Cardiovascular Research 41 (1999) 25 – 40
velocity. The MAP assumes a triangular shape. As ischemia progresses further, the MAP often exhibits an
alternans in amplitude and duration. This alternans is very
typical of severe ischemia and has been linked to the
development of ischemic tachyarrhythmias [72,74,75]. The
mechanism of this ischemia-induced action potential alternans has been related to inadequate electrical restitution
from one depolarization to the next [76] and, consequently,
develops earlier at faster heart rates [77]. Because the
close-bipolar MAP recording detects these changes with
high sensitivity and local resolution, this technique may
help identify areas of ischemic, yet still viable, myocardium.
9.2. MAP recordings for monitoring radiofrequency
energy ( RF) ablation
Successful RF ablation relies on several objectives.
These include (1) identification of the arrhythmia substrate, (2) ascertainment of stable contact between the
ablation electrode and the target myocardium and (3)
successful ablation of the target. Incorporating a MAP
electrode into a RF ablation electrode [4] may serve at
least two of these three objectives. [1] Because MAPs are
obtained only when the catheter tip electrode is in close
and stable contact with viable myocardium, a stable MAP
recording identifies steady contact between the ablation
catheter tip electrode and the endocardial surface [2]. As
the myocardium underneath the RF electrode gets destroyed during the process of RF application, the local
MAP recording mirrors successful destruction by a rapid
loss in MAP amplitude (Fig. 11) [4]. The third objective
(identifying the arrhythmia substrate) may also be accomplished in specific cases [4].
9.3. MAP recordings for monitoring myocardial drug
absorption
Antiarrhythmic drugs are administered to patients via
oral or i.v. routes, based on empiric dosing regimens. Drug
blood levels, while easily obtained, are not available at the
time of electrophysiological study of the patient; besides,
serum drug levels are known to correlate poorly with
antiarrhythmic drug efficacy. Furthermore, it is unknown
to what extent myocardial drug uptake occurs and whether
or not it occurs uniformly within the heart tissue. It would
be advantageous to have a method that provides instantaneous feedback on local myocardial drug effect. Because
many antiarrhythmic agents have distinct effects on
myocardial repolarization (especially class 3 agents), MAP
recordings are ideally suited to measure this effect in situ
directly at the myocardial surface [78]. Unlike the body
surface ECG, which reflects global electrical activity of the
heart, MAP recordings can detect repolarization changes at
individual areas and thereby determine whether drug
uptake is uniform or heterogeneous. This has recently been
Fig. 11. Effect of radiofrequency energy (RF) on MAP signal recorded with an electrode embedded in the tip of the RF electrode. See text for discussion.
From Franz [4].
M.R. Franz / Cardiovascular Research 41 (1999) 25 – 40
demonstrated for amiodarone and its primary metabolite
desethylamiodarone, both of which exhibited heterogeneous myocardial uptake. This heterogeneous uptake was
identified reliably by an equally heterogeneous change in
MAP duration [79].
9.4. MAP recordings during atrial and ventricular
fibrillation
Atrial (AF) and ventricular (VF) fibrillation are characterized by highly irregular patterns of activation and
repolarization. A good agreement between TAP and MAP
recordings during VF has been shown in the isolated rabbit
heart [80]. MAP recordings have an advantage over
electrogram recordings in that they allow distinction of
activation and repolarization and can visualize the excitable gap even during VF or AF (Fig. 12). This has aided
attempts to capture atrial myocardium during AF by
overdrive pacing [81].
MAP recordings are useful for monitoring and understanding the induction and termination of VF during
defibrillator testing. MAP recordings during induction of
VF by T wave shocks have suggested that successful
initiation of fibrillation depends on sufficient dispersion of
ventricular repolarization immediately following the T
wave shock. In concordance with this dispersion mechanism, it has been shown that successful defibrillation
depends on sufficient shock-induced resynchronization of
repolarization [82–85].
Acute MAP recordings are also useful for the distinction
of different types of AF and to better differentiate some
forms of atrial flutter from AF. MAP recordings have
provided clues to the mechanism of terminating atrial
flutter by antiarrhythmic drugs [86]. Recently, MAP
37
recordings have demonstrated the effects of electrical
remodeling caused by sustained AF or atrial flutter in
patients [87].
A limitation of MAP recordings during AF or VF is that
the MAP electrode records the responses of a multitude of
cells at the same time, giving rise to summation potentials
that may differ from single cell recordings under conditions of extreme local dispersion of activation and
repolarization. For instance, the ‘fractionated’ MAP sequence seen in Fig. 12 might very well be the result of
multicellular summation. During AF (or VF), multiple
wavelets are present simultaneously and one recording site
may be influenced by two or three different wavelets
travelling in the neighborhood of the MAP electrode.
9.5. MAP recordings as a means of elucidating the
mechanism of torsade de pointes arrhythmias
Torsade de pointes arrhythmias occur in a variety of
acquired and familial long QT syndromes. The exact
electrophysiologic mechanism of torsades de pointes (TdP)
is under intense investigation. No isolated animal heart
model of this particular arrhythmia exists. A recently
developed model uses multiple simultaneous epicardial and
endocardial MAPs and a volume-conducted 12-lead ECG
in the isolated rabbit heart [39]. Sotalol prolonged repolarization and increased dispersion of ventricular repolarization compared to baseline recordings. With the onset of
low potassium and magnesium concentrations, repolarization was further prolonged and dispersion of repolarization
was further increased followed by the occurrence of early
afterdepolarizations (EADs) in the majority of MAP
recordings, i.e., at both endocardial and epicardial locations of both ventricles. Torsade de pointes observed in
Fig. 12. MAP recordings during atrial fibrillation (AF). Two simultaneous MAP recordings are shown, one from the high right atrium (HRA), the other
from the low right atrium (LRA). Both recordings show activation and repolarization out-of-sync from one another. There is high frequency AF with
intermittent fragmentation of MAPs as well as clearly visible diastolic intervals that are considered to be excitable gaps.
38
M.R. Franz / Cardiovascular Research 41 (1999) 25 – 40
this new isolated heart model was associated with markedly increased dispersion of ventricular repolarization and the
occurrence of EADs in multiple locations of the heart.
[13]
[14]
10. Conclusion
[15]
MAP recordings have come a long way and are now an
integral part of clinical electrophysiological studies
concerned with understanding basic electrophysiology and
arrhythmia mechanisms in the intact heart, including those
of patients. MAP recordings in the clinical laboratory have
confirmed many basic electrophysiological principles, and
observations from human heart MAP recordings have
spawned experimental research not previously recognized
as being clinically important. However, while the methodology of MAP recording by contact electrode technique
is relatively simple, the understanding of the abilities and
limitations of the MAP and its proper interpretations are
not. Future developments and refinements of the MAP
recording technique will undoubtedly advance our possibilities further, including possibly longer-term and simultaneous multiple-site MAP mapping.
[16]
[17]
[18]
[19]
[20]
[21]
References
[22]
[1] Hoffman BF, Cranefield PF, Lepeschkin E, Surawicz B, Herrlich
HC. Comparison of cardiac monophasic action potentials recorded
by intracellular and suction electrodes. Am J Physiol
1959;196:1297–1301.
[2] Franz MR, Burkhoff D, Spurgeon H, Weisfeldt ML, Lakatta EG. In
vitro validation of a new cardiac catheter technique for recording
monophasic action potentials. Eur Heart J 1986;7:34–41.
[3] Ino T, Karagueuzian HS, Hong K, et al. Relation of monophasic
action potential recorded with contact electrode to underlying
transmembrane action potential properties in isolated cardiac tissues:
a systematic microelectrode validation study. Cardiovasc Res
1988;22:255–264.
[4] Franz MR. Bridging the gap between basic and clinical electrophysiology: what can be learned from monophasic action potential recordings?. J Cardiovasc Electrophysiol 1994;5:699–710.
[5] Sicouri S, Antzelevitch C. Electrophysiologic characteristics of M
cells in the canine left ventricular free wall. J Cardiovasc Electrophysiol 1995;6:591–603.
[6] Antzelevitch C, Nesterenko VV, Yan GX. Role of M cells in
acquired long QT syndrome, U waves, and torsade de pointes. J
Electrocardiol 1995;28(Suppl):131–138.
[7] Burdon-Sanderson J, Page FJM. On the time-relations of the
excitatory process in the ventricle of the heart of the frog. J Physiol
1882;2:385–412.
¨ E. Elektrophysiologie des Herzens bei einphasischer Ab[8] Schutz
leitung. Ergebn Physiol Exper Pharmakol 1936;38:493–620.
¨ E. Weitere Versuche mit einphasischer Aufzeichnung des
[9] Schutz
¨
Warmbluter-Elektrokardiogramms.
Z Biol 1934;95:78–90.
[10] Korsgren M, Leskinen E, Sjostrand U, Varnauskas E. Intracardiac
recording of monophasic action potentials in the human heart. Scand
J Clin Lab Invest 1966;18:561–564.
[11] Olsson SB. Atrial repolarization in man. Effect of beta-receptor
blockade. . Br Heart J 1974;36:806–810.
[12] Brorson L, Olsson SB. Atrial repolarization in healthy males.
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
Studies with programmed stimulation and monophasic action potential recordings. Acta Med Scand 1976;199:447–454.
Olsson SB. Monophasic action potentials from right atrial muscle
recorded during heart catheterization. Acta Med Scand
1971;190:369–379.
Jochim K, Katz LN, Mayne W. The monophasic electrogram
obtained from the mammalian heart. Am J Physiol 1935;111:177–
186.
Franz M, Schottler M, Schaefer J, Seed WA. Simultaneous recording
of monophasic action potentials and contractile force from the
human heart. Klin Wochenschr 1980;58:1357–1359.
Franz MR. Long-term recording of monophasic action potentials
from human endocardium. Am J Cardiol 1983;51:1629–1634.
Franz MR, Flaherty JT, Platia EV, Bulkley BH, Weisfeldt ML.
Localization of regional myocardial ischemia by recording of
monophasic action potentials. Circulation 1984;69:593–604.
Franz MR, Bargheer K, Rafflenbeul W, Haverich A, Lichtlen PR.
Monophasic action potential mapping in human subjects with
normal electrocardiograms: direct evidence for the genesis of the T
wave. Circulation 1987;75:379–386.
Franz MR, Costard A. Frequency-dependent effects of quinidine on
the relationship between action potential duration and refractoriness
in the canine heart in situ. Circulation 1988;77:1177–1184.
Franz MR, Swerdlow CD, Liem LB, Schaefer J. Cycle length
dependence of human action potential duration in vivo. Effects of
single extrastimuli, sudden sustained rate acceleration and deceleration, and different steady-state frequencies. J Clin Invest
1988;82:972–979.
Schaefer H. Theorie des potentialabgriffs beim elektrokardiogramm,
auf der grundlage der ‘membrantheorie’. Pflug Arch Eur J Physiol
1942;245:72–97.
˜ A, Scholmerich
¨
Schaefer H, Pena
P. Der monophasische aktions¨
strom von spitze und basis des warmbluterherzens
und die theorie
der T-welle des EKG. Pflug Arch Eur J Physiol 1943;246:728–745.
Sugarman H, Katz LN, Sanders A, Jochim K. Observations on the
genesis of the electrical currents established by injury to the heart.
Am J Physiol 1940;130:130–143.
Cranefield PF, Eyster JAE, Gilson WE. Electrical characteristics of
injury potentials. Am J Physiol 1951;167:450–457.
Eyster JAE, Gilson WE. The development and contour of cardiac
injury potential. Am J Physiol 1946;145:507–520.
Antzelevitch C, Moe GK. Electrotonically mediated delayed conduction and reentry in relation to ‘slow responses’ in mammalian
ventricular conducting tissue. Circ Res 1981;49:1129–1139.
Franz MR. Method and theory of monophasic action potential
recording. Prog Cardiovasc Dis 1991;33:347–368.
Coronel R, Wilms-Schopman FJ, Opthof T, van Capelle FJ, Janse
MJ. Injury current and gradients of diastolic stimulation threshold,
TQ potential, and extracellular potassium concentration during acute
regional ischemia in the isolated perfused pig heart. Circ Res
1991;68:1241–1249.
Levine JH, Moore EN, Kadish AH, Guarnieri T, Spear JF. The
monophasic action potential upstroke: a means of characterizing
local conduction. Circulation 1986;74:1147–1155.
Koller B, Franz MR. New classification of moricizine and propafenone based on electrophysiologic and electrocardiographic data
from isolated rabbit heart. J Cardiovasc Pharmacol 1994;24:753–
760.
Franz MR, Burkhoff D, Lakatta EG, Weisfeldt ML. Monophasic
action potential recording by contact electrode technique: In vitro
validation and clinical applications. In: Butrous GS, Schwartz PJ,
editors. Clinical aspects of ventricular repolarization. London:
Farrand Press, 1989:81–92.
Draper MH, Weidmann S. Cardiac resting and action potentials
recorded with an intracellular electrode. J Physiol 1951;115:74–94.
Tande PM, Mortensen E, Refsum H. Rate-dependent differences in
dog epi- and endocardial monophasic action potential configuration
in vivo. Am J Physiol 1991;261:H1387–H1391.
M.R. Franz / Cardiovascular Research 41 (1999) 25 – 40
[34] Patterson E, Szabo B, Scherlag BJ, Lazzara R. Early and delayed
afterdepolarizations associated with cesium chloride-induced arrhythmias in the dog. J Cardiovasc Pharmacol 1990;15:323–331.
[35] Ben-David J, Zipes DP. Differential response to right and left ansae
subclaviae stimulation of early afterdepolarizations and ventricular
tachycardia induced by cesium in dogs. Circulation 1988;78:1241–
1250.
[36] Priori SG, Corr PB. Mechanisms underlying early and delayed
afterdepolarizations induced by catecholamines. Am J Physiol
1990;258:H1796–H1805.
[37] Vera Z, Pride HP, Zipes DP. Reperfusion arrhythmias: role of early
afterdepolarizations studied by monophasic action potential recordings in the intact canine heart during autonomically denervated and
stimulated states. J Cardiovasc Electrophysiol 1995;6:532–543.
[38] Vos MA, Verduyn SC, Gorgels AP, Lipcsei GC, Wellens HJ.
Reproducible induction of early afterdepolarizations and torsade de
pointes arrhythmias by D-sotalol and pacing in dogs with chronic
atrioventricular block. Circulation 1995;91:864–872.
[39] Zabel M, Hohnloser SH, Behrens S, et al. Electrophysiologic
features of torsades de pointes: insights from a new isolated rabbit
heart model. J Cardiovasc Electrophysiol 1997;8:1148–1158.
[40] Habbab MA, el-Sherif N. Drug-induced torsades de pointes: role of
early afterdepolarizations and dispersion of repolarization. Am J
Med 1990;89:241–246.
[41] Morgan JM, Lopes A, Rowland E. Sudden cardiac death while
taking amiodarone therapy: the role of abnormal repolarization. Eur
Heart J 1991;12:1144–1147.
[42] El-Sherif N, Bekheit SS, Henkin R. Quinidine-induced long QTU
interval and torsade de pointes: role of bradycardia-dependent early
afterdepolarizations. J Am Coll Cardiol 1989;14:252–257.
[43] Shimizu W, Ohe T, Kurita T, Tokuda T, Shimomura K. Epinephrineinduced ventricular premature complexes due to early afterdepolarizations and effects of verapamil and propranolol in a patient with
congenital long QT syndrome. J Cardiovasc Electrophysiol
1994;5:438–444.
[44] Shimizu W, Ohe T, Kurita T, et al. Effects of verapamil and
propranolol on early afterdepolarizations and ventricular arrhythmias
induced by epinephrine in congenital long QT syndrome. J Am Coll
Cardiol 1995;26:1299–1309.
[45] Lab MJ. Contraction–excitation feedback in myocardium. Physiological basis and clinical relevance. Circ Res 1982;50:757–766.
[46] Lab MJ. Monophasic action potentials and the detection and
significance of mechanoelectric feedback in vivo. Prog Cardiovasc
Dis 1991;34:29–35.
[47] Lerman BB, Burkhoff D, Yue DT, Franz MR, Sagawa K. Mechanoelectrical feedback: independent role of preload and contractility
in modulation of canine ventricular excitability [published erratum
appeared in J Clin Invest 1986;77:2053]. J Clin Invest
1985;76:1843–1850.
[48] Lerman BB, Burkhoff D, Yue DT, Franz MR, Sagawa K. Mechanoelectrical feedback: independent role of preload and contractility
in modulation of canine ventricular excitability. J Clin Invest
1985;76:1843–1850.
[49] Franz MR, Burkhoff D, Yue DT, Sagawa K. Mechanically induced
action potential changes and arrhythmia in isolated and in situ
canine hearts. Cardiovasc Res 1989;23:213–223.
[50] Franz MR, Cima R, Wang D, Profitt D, Kurz R. Electrophysiological
effects of myocardial stretch and mechanical determinants of
stretch-activated arrhythmias [published erratum appeared in Circulation 1992;86:1663]. Circulation 1992;86:968–978.
[51] Franz MR, Cima R, Wang D, Profitt D, Kurz R. Electrophysiological
effects of myocardial stretch and mechanical determinants of
stretch-activated arrhythmias. Circulation 1992;86:968–978.
[52] Zabel M, Koller BS, Sachs F, Franz MR. Stretch-induced voltage
changes in the isolated beating heart: importance of the timing of
stretch and implications for stretch-activated ion channels. Cardiovasc Res 1996;32:120–130.
39
[53] Franz MR. Mechano-electrical feedback in ventricular myocardium.
Cardiovasc Res 1996;32:15–24.
[54] Fasciano RW, Tung L. Is stretch-induced depolarization the basis of
contact electrode recordings? (Abstract). Circulation 1995;92(Suppl
I):I–299.
[55] Housmans PR, Chuck LH, Claes VA, Brutsaert DL. Nonuniformity
of contraction and relaxation of mammalian cardiac muscle. Adv
Exp Med Biol 1984;170:837–840.
[56] Olsson SB, Blomstrom P, Blomstrom-Lundqvist C, Wohlfart B.
Endocardial monophasic action potentials. Correlations with intracellular electrical activity. Ann NY Acad Sci 1990;601:119–127.
[57] Olsson SB. Right ventricular monophasic action potentials during
regular rhythm. A heart catheterization study in man. Acta Med
Scand 1972;191:145–157.
[58] Franz MR, Kirchhof PF, Fabritz CL, Zabel M. Computer analysis of
monophasic action potentials: manual validation and clinically
pertinent applications. Pacing Clin Electrophysiol 1995;18:1666–
1678.
[59] Yuan S, Wohlfart B, Olsson SB, Blomstrom-Lundqvist C. Clinical
application of a microcomputer system for analysis of monophasic
action potentials. Pacing Clin Electrophysiol 1996;19:297–308.
[60] Franz MR, Chin MC, Sharkey HR, Griffin JC, Scheinman MM. A
new single catheter technique for simultaneous measurement of
action potential duration and refractory period in vivo. J Am Coll
Cardiol 1990;16:878–886.
[61] Lee RJ, Liem LB, Cohen TJ, Franz MR. Relation between repolarization and refractoriness in the human ventricle: cycle length
dependence and effect of procainamide. J Am Coll Cardiol
1992;19:614–618.
[62] Hondeghem LM. Antiarrhythmic agents: modulated receptor applications. Circulation 1987;75:514–520.
[63] Costard-Jaeckle A, Liem LB, Franz MR. Frequency-dependent
effect of quinidine, mexiletine, and their combination on postrepolarization refractoriness in vivo. J Cardiovasc Pharmacol
1989;14:810–817.
[64] Costard-Jackle A, Franz MR. Frequency-dependent antiarrhythmic
drug effects on postrepolarization refractoriness and ventricular
conduction time in canine ventricular myocardium in vivo. J
Pharmacol Exp Ther 1989;251:39–46.
[65] Sicouri S, Fish J, Antzelevitch C. Distribution of M cells in the
canine ventricle. J Cardiovasc Electrophysiol 1994;5:824–837.
[66] Sicouri S, Antzelevitch C. Drug-induced afterdepolarizations and
triggered activity occur in a discrete subpopulation of ventricular
muscle cells (M cells) in the canine heart: quinidine and digitalis. J
Cardiovasc Electrophysiol 1993;4:48–58.
[67] Nesterenko VV, Weissenburger J. Experimental evidence for reinterpretation of basis for the monophasic action potential: a new
technique with large amplitude and stable transmural signals.
(Abstract). Circulation 1995;92(Suppl-I):I–299.
[68] De Mello WC, Motta GE, Chapeau M. A study on the healing-over
of myocardial cells of toads. Circ Res 1969;24:475–487.
[69] De Mello WC. Effect of intracellular injection of calcium and
strontium on cell communication in heart. J Physiol 1975;250:231–
245.
[70] De Mello WC. Influence of the sodium pump on intercellular
communication in heart fibres: effect of intracellular injection of
sodium ion on electrical coupling. J Physiol 1976;263:171–197.
[71] De Mello WC. The role of cAMP and Ca on the modulation of
junctional conductance: an integrated hypothesis. Cell Biol Int Rep
1983;7:1033–1040.
[72] Mohabir R, Franz MR, Clusin WT. In vivo electrophysiological
detection of myocardial ischemia through monophasic action potential recording. Prog Cardiovasc Dis 1991;34:15–28.
[73] Janse MJ. Electrophysiological effects of myocardial ischaemia.
Relationship with early ventricular arrhythmias. Eur Heart J
1986;7(Suppl A):35–43.
[74] Downar E, Janse MJ, Durrer D. The effect of acute coronary artery
40
[75]
[76]
[77]
[78]
[79]
[80]
[81]
M.R. Franz / Cardiovascular Research 41 (1999) 25 – 40
occlusion on subepicardial transmembrane potentials in the intact
porcine heart. Circulation 1977;56:217–224.
Nearing BD, Huang AH, Verrier RL. Dynamic tracking of cardiac
vulnerability by complex demodulation of the T wave. Science
1991;252:437–440.
Kurz RW, Mohabir R, Ren XL, Franz MR. Ischaemia induced
alternans of action potential duration in the intact heart: dependence
on coronary flow, preload and cycle length. Eur Heart J
1993;14:1410–1420.
Kurz RW, Ren XL, Franz MR. Dispersion and delay of electrical
restitution in the globally ischaemic heart. Eur Heart J 1994;15:547–
554.
Platia EV, Weisfeldt ML, Franz MR. Immediate quantitation of
antiarrhythmic drug effect by monophasic action potential recording
in coronary artery disease. Am J Cardiol 1988;61:1284–1287.
Franz MR, Behrens S, Li C. Myocardial tissue concentrations of
amiodarone and desethylamiodarone after chronic treatment: Correlation with local action potential duration. (Abstract). J Am Coll
Cardiol 1997;29(supple):344A.
Kirchhof PF, Fabritz CL, Coronel R, Opthof T, Janse MJ. Interpretation of monophasic action potentials during ventricular fibrillation:
comparison with intracellular recordings. (Abstract). Eur Heart J
1995;16(suppl):272.
Pandozi C, Bianconi L, Villani M, et al. Local capture by atrial
pacing in spontaneous chronic atrial fibrillation. Circulation
1997;95:2416–2422.
[82] Fabritz CL, Kirchhof PF, Behrens S, Zabel M, Franz MR. Myocardial vulnerability to T wave shocks: relation to shock strength, shock
coupling interval, and dispersion of ventricular repolarization. J
Cardiovasc Electrophysiol 1996;7:231–242.
[83] Kirchhof PF, Fabritz CL, Zabel M, Franz MR. The vulnerable
period for low and high energy T-wave shocks: role of dispersion of
repolarisation and effect of D-sotalol. Cardiovasc Res 1996;31:953–
962.
[84] Kirchhof PF, Fabritz CL, Behrens S, Franz MR. Induction of
ventricular fibrillation by T-wave field-shocks in the isolated perfused rabbit heart: role of nonuniform shock responses. Basic Res
Cardiol 1997;92:35–44.
[85] Behrens S, Li C, Fabritz CL, Kirchhof PF, Franz MR. Shockinduced dispersion of ventricular repolarization: implications for the
induction of ventricular fibrillation and the upper limit of vulnerability. J Cardiovasc Electrophysiol 1997;8:998–1008.
[86] Stambler BS, Wood MA, Ellenbogen KA. Pharmacologic alterations
in human type I atrial flutter cycle length and monophasic action
potential duration. Evidence of a fully excitable gap in the reentrant
circuit. J Am Coll Cardiol 1996;27:453–461.
[87] Franz MR, Karasik PL, Li C, Moubarak J, Chavez M. Electrical
remodeling of the human atrium: similar effects in patients with
chronic atrial fibrillation and atrial flutter. J Am Coll Cardiol
1997;30:1785–1792.