Download Earl Wood–A research career noted for development of novel

J Appl Physiol 117: 945–956, 2014.
First published September 4, 2014; doi:10.1152/japplphysiol.00491.2014.
Synthesis Review
Earl Wood–A research career noted for development of novel instruments
driven by the power of the indicator dilution concept
Erik L. Ritman
Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota
Submitted 5 June 2014; accepted in final form 13 August 2014
oximetry; computed tomography; innovation; X-ray fluoroscopy; cardiovascular
EARL WOOD (FIG. 1) DIED
in 2009 at age 96. He worked at the
Mayo Clinic from 1942 to 1982 when regulations required him
to retire at age 70. Detailed descriptions of his many accolades
and the broad reach of his many diverse achievements are
listed in several obituaries, such as those provided in the March
27 New York Times (66a) and by the American Physiological
Society (http://the-aps.org/mm/Membership/Obituaries/wood.
html) (2). Briefly, Earl Wood’s research interests ranged from
the cellular level (1, 49, 60, 101) to intact animal and human
studies under pathophysiological and artificially induced physiological stress (99). However, a common thread in all of his
research involved development of novel instrumentation to
provide the necessary data (5, 12, 13, 24, 28, 31, 32, 47, 73, 78,
81, 91, 100, 102, 105, 106, 108, 109).
Methods for fostering innovation are not well understood in
that they often emerge from research and developments not
specifically targeted at the problem of interest (10). There are
two basic aspects to innovation, one is T. Kuhn’s proposition
(50) of replacement of one idea with another [e.g., Darwin’s
Address for reprint requests and other correspondence: E. L. Ritman, Dept.
of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine,
200 First St. SW, Rochester, MN 55905 (e-mail: [email protected]).
http://www.jappl.org
Natural Selection (16) replaced J.-B. Lamarck’s (52) inheritance hypothesis] and the other is E. Nagel’s (63) development
of instrumentation for deeper insights into natural phenomena.
The two are obviously interrelated. There are three approaches
to instrument development, one is opportunistic [e.g., Baldwin
(4a)], the second involves progressive refinement of an instrument [e.g., the combustion engine automobile (18)], and the
third pursues a continued quest to perfect a particular function
(e.g., public transportation). This overview of Earl Wood’s
research career indicates that much of his research falls under
this third category in that it was driven by his quest to perfect
the indicator dilution method.
TIME SEQUENCE OF EARL WOOD’S DEVELOPMENT OF
INSTRUMENTS TO MORE ACCURATELY MEASURE
CARDIOVASCULAR INDICATOR DILUTION CURVES
Earl Wood’s career at Mayo can be divided into four stages:
his human centrifuge years (1942–1945); his cardiac catheterization laboratory years (1946 –1961); his years as a freelance
investigator developing electronic X-ray image-based methodology to increase the accuracy of dye dilution methodology and
its relationship to other relevant signals of cardiovascular
structure and function (1962–1973); and the final period
8750-7587/14 Copyright © 2014 the American Physiological Society
945
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Ritman EL. Earl Wood–A research career noted for development of novel instruments
driven by the power of the indicator dilution concept. J Appl Physiol 117: 945–956, 2014.
First published September 4, 2014; doi:10.1152/japplphysiol.00491.2014.—During World
War 2, Earl Wood was charged with elucidating the biomedical factors in acceleration-induced loss of consciousness experienced by pilots in high-performance
aircraft. For this, he developed devices for measurement and recording of blood
pressure and tissue blood content. Those data lead to the design and fabrication of
successful countermeasures to acceleration-induced loss of consciousness with an
inflatable “G-suit” and “M1” breath-holding maneuver. After World War 2, he
utilized and modified these instruments and made use of indicator dilution techniques by continuous intracardiac blood sampling to greatly increase the specificity
and sensitivity of diagnosis of intracardiac anatomic and functional abnormalities in
patients with congenital heart disease. This contributed to the greatly increased
success rate of open-heart surgery in the 1950s. In the 1960s, he built on the then
recently available video-coupled electronic X-ray image intensifier to develop
X-ray fluoroscopy-based recording of indicator dilution signals in all cardiac
chambers and surrounding great vessels without the need for placing catheter tips
at those locations for blood sampling. However, these blood flow-related data were
of limited value, as they were not measured concurrent with myocardial functional
demand for perfusion. In the 1970s, he overcame this limitation by developing a
high-speed multislice X-ray imaging scanner to provide tomographic images of
concurrent dynamic cardiac anatomy and the indicator dilution-based estimates of
blood flow distributions. On his retirement at age 70 in 1982, he had accomplished
his 2 decade-old goal of the ability to make accurate concurrent, minimally
invasive, and indicator dilution-based measurement of cardiovascular structure to
function relationships.
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Fig. 1. A sketch of Earl Wood made in the early 1960s.
(1974 –1982), which was devoted to the development and use
of high-speed, multislice computed tomography (CT), which
overcame major restrictions inherent in projection X-ray imaging for measuring concurrent dye dilution curves and dynamic anatomy.
Epoch 1 (1942–1945)
Earl Wood was hired in 1942 to use the Mayo Human
Centrifuge to establish the cause of acceleration-induced loss
of consciousness (G-LOC). The centrifuge was designed to
emulate the sudden increase in head-to-foot G forces resulting
from rapid changes in direction of fighter planes and dive
bombers (54, 103). Note that, because of many of the developments being classified at the time, their detailed description
was only possible well after the end of hostilities. Figure 2 is
a photograph of that centrifuge with a subject about to be
exposed to the increased G force and the central observer (Earl
Wood) who could stop the centrifuge should there be a medical
problem. The loss of consciousness was attributed to inadequate blood supply to the brain caused by one of two plausible
mechanisms. One was venous pooling in the lower body,
which, in turn, reduced blood supply to the heart, so that there
was insufficient cardiac output to provide blood flow to the
brain. The other was that the left ventricle (LV) could not
increase its blood pressure (BP) enough to overcome the
increased hydrostatic pressure gradient generated by the G
force on the arterial blood column between the head and the
heart.
The venous pooling hypothesis was addressed by surrounding the lower body with water so that the increase in hydrostatic pressure in the water would match that increase in the
veins, and hence this pooling would be eliminated. The “Iron
Maiden,” a metal bath filled with water, did not increase G
tolerance significantly and thereby eliminated that as a source
to pursue (104).
The other hypothesis was based on the fact that the arterial
BP at head level, with the head at a nominal 40 cm above the
heart, decreased in proportion to the G force. If the LV
generated 120-mmHg BP, then at 1 G the BP at head level
would be 90 mmHg. However, at 4 G the BP at the head would
be 0 mmHg, resulting in G-LOC. Two instruments were
developed to test this hypothesis. One is a pressure-measuring
transducer (Fig. 3) made suitable for use with a fluid-filled
intravascular catheter. This was used to measure BP at heart
level and at head level by holding one catheterized radial artery
in the wrist at heart and the other wrist at head level, respectively (6, 55). The other instrument that was developed was an
earpiece device that measured the blood content of tissue by
Fig. 3. Photograph of an intra-arterial pressure measuring device developed for
use in monitoring intravascular blood pressure. This device generated an
electric signal proportional to the pressure across a thin, flexible membrane.
The membrane was one of the four resistances of a Wheatstone Bridge
arrangement. The distortion of the membrane changed its electrical resistance.
[Courtesy of Dr. Phillip Dow, Dept. of Physiology, Medical College of
Georgia.]
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Fig. 2. Photo of centrifuge with Earl Wood at center to act as observer and
subject in gondola before starting the rotation. The 40-ton fly wheel would
have been brought up to the rotation speed for the selected G value. To start
the centrifuge rotation, a clutch mechanism grabbed the fly wheel so that it
came up to speed rapidly to emulate the rapid flight maneuvers experienced by
pilots. [Reprinted from Wood (92) with permission.]
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increased LV pressure) were developed to maintain the increased aortic BP needed to maintain consciousness (97, 98).
Epoch 2 (1946 –1960)
use of infrared transmission (Fig. 4). This was an additional
means of detecting blood flow to the head (61).
Another instrument that was developed was a multichannel
signal recorder (Fig. 5). Note the decrease in BP at head level
and reduced ear lobe blood volume recorded concurrently
along with other vital signals. As a consequence of these data,
the G suit (which compressed arteries in the limbs, thereby
increasing aortic BP) and M1 breath-holding maneuver (which
Fig. 5. A typical multichannel tracing of sensor signals
obtained from an instrumented subject performing tasks (to
show he was conscious) while riding the centrifuge. This
recording shows the multisignal recording during exposure
to 4.6 G without a G suit. Note the precipitous drop in blood
pressure at head level (measured by holding the catheterized
radial artery at head level) compared with the little change
(indeed some increase toward the end of the “run”) at heart
level (measured by holding the other catheterized radial
artery at heart level). The earpiece signal showed a precipitous drop in ear lobe blood volume in parallel to the arterial
blood pressure at head level. The loss of the subject’s
acknowledgment that a light was observed indicates the
period of loss of consciousness. [Reprinted from Lambert
(53) with permission.]
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Fig. 4. Photograph of an earpiece oximetry device. It shone a red light through
the ear lobe. The hemoglobin in the vasculature of that ear lobe selectively
absorbed the light so that the electrical signal generated by the red light sensor
was proportional to the blood content of the ear lobe. This sensor could also
provide a signal proportional to the oxygen saturation of the hemoglobin.
[Reprinted from Wood et al. (104) with permission.]
Thus at the end of the war the mission was accomplished,
but what now? It turned out that at about this time open-heart
surgery was made possible by the development of the heartlung bypass machine (27), as well as antibiotics. Unfortunately, the success rate was very poor, in large measure
because of inaccurate diagnosis of the anatomic problem (89,
96). The instruments Earl Wood developed for monitoring
cardiovascular parameters for use on the centrifuge work were
seen as a way to increase diagnostic accuracy. Of special note
is the incidental observation that the earpiece device for monitoring tissue blood content showed a change in signal due to
the passage of a bolus of intravascular saline injected to flush
the needle in the radial artery. This was seen as the basis for
utilizing the shape and time distribution of indicator dilution
curves to demonstrate the presence of intracardiac anatomic
short circuits. Moreover, as such shunts often resulted in
nonoxygenated blood mixing with oxygenated blood, the oxygen content of blood was decreased, resulting in “blue”
babies. For this reason, the earpiece was modified to allow
monitoring hemoglobin oxygenation state by continuous withdrawal of blood through a catheter positioned in selected sites
within or near the heart and passing it through the oximeter
(11, 14). At that time, Evans blue dye was commonly used for
generating a dye curve rather than saline, as it generated a
much more obvious dilution curve than did saline. The prob-
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lem though was that, in congenital heart disease, the blood is
poorly oxygenated (blue babies), and hence even the Evans
Blue curve could be of reduced specificity and accuracy (64).
Dr. Irwin (I. J.) Fox (22), a Fellow in the Laboratory, worked
with Kodak Company chemists to develop a green dye that was
not affected by the oxygen concentrations so that quantitative
dilution curves could be obtained. This made the diagnostic
procedures of much increased accuracy and contributed to the
increasing success of the surgery. A short circuit, such as
caused by an atrial septal defect or by a ventricular septal
defect, could now be diagnosed by virtue of the early arrival of
the dye curve (Fig. 6). Nonetheless, the differences between
these curves, while generally diagnostic, were not always
sufficiently different to distinguish between some anatomic
malformations. This problem was in part attributed to the
“blurring” of the dilution curve caused by the passage of the
sampled blood through the narrow lumen of the sampling
catheter (23).
The problem of the “blurring” of the blood-drawn catheter
was addressed by a number of investigators over the next
decade or so (75). This stimulated Earl Wood to find a way to
overcome this blurring. Figure 7 illustrates how measurement
of the blurring function of the catheter could be used to “undo”
the blurring by the catheter (30). Although this manual deconvolution process (no digital computers were available for this
purpose) could undo much of the blurring, it introduced spurious signals (“ringing”) due to the sparse sampling of the
dilution curve deflections used in the mathematical processing
of the blurring dye dilution curve. This approach was rejected
because it could not be done in real time during the catheterization process, hence other means of circumventing the blurring problem needed to be pursued.
The X-ray fluoroscopy, then in use, consisted of a fluorescent screen, which was observed by the dark-adapted eye. This
could help in placing catheters in and near the heart, but there
was no method for recording those fluoroscopic images. However, in the late 1950s, electronic X-ray image intensifiers
became available (9) and allowed photographic film-based
cineangiographic recordings to be made during the passage of
a bolus of intravascularly injected X-ray contrast agent through
the heart. While this allowed direct identification of some
intracardiac anatomic abnormalities, it also allowed generation
of indicator dilution curves at any location within the heart
without the blurring due to catheter sampling (Fig. 8). Unfortunately, this approach also was impractical, as real-time anal-
Fig. 7. The process of blood being drawn through a
narrow-lumen sampling catheter “blurred” the dye
dilution curve. This “filtering” is illustrated by the
delay, loss of amplitude, and broadening of the
curve obtained by the sampling catheter (right)
compared with the curve at the injection site (left).
The middle panel shows the “blurring” of a step
function input of dye concentration at the catheter
tip. The blurring of the step function would be used
to “undo” the blurring of the dilution curve. [Reprinted from Parrish et al. (66) with permission.]
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Fig. 6. Schematic representation of the change in shape and timing of the dye dilution curves caused by different intracardiac anatomic short circuits. Despite
the subtleties of the changes in the curves, this provided a major advance in the diagnostic accuracy of cardiac anatomy in congenital heart disease. [Left panel:
reprinted from Fox and Wood (25) with permission; right panel: reprinted from Wood (93) by permission of Mayo Foundation for Medical Education and
Research. All rights reserved.]
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Fig. 8. Dilution curves of passage of a bolus of intravascular contrast agent as
conveyed by a catheter withdrawal system and by cine densitometry. The
cine-based curve was obtained by recording a cine film at many points in time
per second during X-ray fluoroscopy. From this cine sequence, the cine film
brightness was sampled for every sequential heart cycle. Note that the “blurring” of the catheter-drawn curve is not present in the cine-based curve.
Epoch 3 (1961–1976)
This decade involved three major events that determined the
direction of Earl Wood’s future career. First was his being
awarded the coveted American Heart Association Career Investigator Award, which made him essentially independent of
Mayo’s somewhat restrictive research policies at the time (59).
His experience in the Cath Lab showed him the power of the
indicator dilution curve in terms of function (i.e., quantitation
of cardiac output, central blood volume and central vascular
and intracardiac short circuits, as well as valve incompetence)
(45, 65, 84).
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The introduction of television fluoroscopy (58) was important because X-ray angiography was shown to generate more
accurate measure of indicator dilution curve timing and concentration. Dr. P. H. Heintzen, a pediatric cardiologist in Kiel
Germany, visited the Lab in the mid-sixties as he too was
starting to use videofluoroscopy imaging for quantitative analysis of cardiac anatomy and function (33). Because of the
promise of television, this led Earl Wood to hire Ralph E.
Sturm, an expert in the field, who had worked on the centrifuge
during the war (80). Sturm was the first to use television to
image Sputnik and to attach a TV camera to an astronomical
telescope at Flagstaff Lowell’s observatory (4). The development of the videotape recorder was critical, as it allowed
repeated, immediate playback of the image during the catheterization procedure so that different areas within the imaged
heart could be analyzed, effectively at the same time within the
one angiographic sequence. This was important in that it
opened the possibility of reducing the need for placing multiple
intravascular sampling catheters within or downstream to the
heart.
Ralph Sturm developed the video-densitometer (82), a device that allowed obtaining indicator dilution curves generated
by the passage of a bolus of injected intravascular contrast
agent. Figure 9 shows video-densitometric analysis of a videofluoroscopic image sequence with a sampling window
position upstream and downstream to the mitral valve. It
shows the simultaneous dye dilution curves in the LV and
left atrial (LA) chambers. The area under the LA curve
shows a marked increase due to development of mitral valve
incompetence due to dilation of the LV chamber, consequent to increased aortic BP.
Figure 10 shows a fluoroscopic image of dye passing
through a saphenous vein bypass graft (77). A sampling window at the proximal and one at the distal end of the graft
generated two curves with different mean transit times. The
difference in those timing values was the transit time of the
bolus of contrast through the graft. The image was also used to
calculate the vein’s lumen volume between these two sampling
site. Its volume divided by the transit time equals flow in the
vein. This information could not be obtained with catheter
sampling without advancing a catheter though the vein to that
distal end, thereby compromising the vein’s lumen volume and
Fig. 9. A photograph of a typical videofluoroscopic image of a ventriculogram. The
opacified left ventricular (LV) chamber
shows as the dark area. Video densitometry
windows over the LV chamber side of the
mitral valve and again on the left atrial (LA)
side of the mitral valve of same angiogram
generated the two contrast dilution curves.
Note that the amplitude of the LA curve
increased with increased arterial vascular resistance caused by infusion of angiotensin.
[Reprinted from Tsakiris et al. (86) with
permission of Mayo Foundation for Medical
Education and Research. All rights reserved.]
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ysis of the cine images could not be performed due to the need
to develop and project the cine film.
The surgeons, however, wanted the catheterization procedures to be performed at Saint Mary’s Hospital close to the
surgical suites (Earl Wood performed them in a suite in the
Medical Sciences Building originally used to prepare the subjects for the centrifuge runs), and also they did not like the
long-duration studies by Earl Wood who made each study a
research protocol. As a consequence, Dr. H. J. C. (Jeremy)
Swan, who was an Associate Professor working in the Laboratory, headed up the new Saint Mary’s Cath Lab. This left Earl
Wood at a loss as to what project he could pursue, and he lost
the stimulation of working with many budding cardiologists
and vascular surgeons (95).
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Fig. 10. Inset shows videofluoroscopic
opacification of a saphenous vein bypass
graft during an aortic root injection of contrast agent. Contrast dilution curves at the
proximal (A) and distal (B) end of that
saphenous vein bypass graft between the
aorta and epicardial coronary artery differ in
appearance and mean transit times. The volume of the graft could be calculated from its
dimensions obtained from that same videofluoroscopic image, and the transit time of
the bolus through the graft allowed calculation of the blood flow by dividing the graft
volume by the bolus transit time. [Reprinted
from Smith et al. (76) with permission.]
Fig. 11. A photograph of a television screen showing a typical videofluoroscopic recording of two concurrent biplane images (in this case of an isolated
working LV). The bar pattern on the left edge of the image was the method
developed to record multiple biological signals recorded concurrent with the
X-ray images. The gray-scale in the bar pattern encoded the signal amplitude,
which could record up to 16 channels, each at 1,000 samples per second.
[Reprinted from Sturm et al. (79) with permission.]
from the fluoroscopy could be accurately and conveniently
registered with those signals. This figure shows a biplane left
ventriculogram so that concurrent LV volumes could also be
measured.
In those days, several methods were used to calculate the
volume of the LV chamber (3). These volumes could be used
to estimate LV ejection fraction and external work [via the LV
chamber pressure-volume loop area (83)], important determinants of the need for perfusion. All methods assumed elliptical
shape for the chamber, and the diameters of the ellipsoids were
estimated from two or more major and minor diameters (41).
These estimates of volume were inaccurate because it poorly
accounted for the altered shape of the ventricle, especially in
disease states. The most accurate method was the Chapman
method (7), which assumed the chamber to be well represented
by a stack of thin elliptical cross sections. The volume of each
cross section would be added using Simpson’s rule. This
method was unfortunately clinically impractical in terms of the
manual work involved (87).
About this time, time-shared mainframe digital computers
became accessible to researchers. On the advice of past laboratory Fellow, Homer Warner, a Control Data Corp. (Bloomington MN) CDC3200 computer was acquired by Earl Wood
with National Institutes of Health (NIH) funding, the second
NIH grant allowed to be submitted by the Mayo establishment.
This computer was able to sample analog signals, support
many individual users via a time-share operating system, and
could generate signals that activated or disabled peripheral
instruments, such as recording apparatus, etc. Using this capability, Ralph Sturm designed the videometer, a device that
sampled each horizontal raster scan line of the video image,
and set off a Schmidt trigger every time the signal crossed
some gray-scale threshold (82). The videodisk, a novelty at the
time developed for the sports industry, made instantaneous
stop-action replay possible so that the desired angiographic
sequence could be sampled under computer control.
Figure 12 shows a stop action video replay from the disk of
the opacified LV chamber. The time interval for the video
horizontal raster sweep to travel from the left edge of the
picture to the Schmidt trigger pulse was recorded by the
computer. Hence, all 200 or so transverse diameters of the LV
chamber in the biplane images could be recorded in real time,
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flow. This technique could also be applied to the coronary
arteries. However, there was a problem in that, if the vein or
artery lumen was not circular in cross section, then the
calculated volume depended on the angle of view relative to
the vein’s different diameters. Moreover, the volume of, and
work performed by, the myocardium perfused by the graft or
coronary artery was not known so that the match (or mismatch) between blood supply and myocardial and cardiac
function could not be answered. Nonetheless, this methodology was used successfully in research studies in the
human Cath Lab (8).
Figure 11 illustrates one of the developments shepherded by
Ralph Sturm and implemented by lab Fellow Dr. P. Osypka
and Mayo engineer R. J. Hansen, who designed and fabricated
a method for simultaneous recording of the two biplane fluoroscopic images within one video display (90). This eliminated
the laborious task of recording two separate images and then
retrospectively matching their timing for analysis. Also, notice
the bar code in the left of the image. It recorded up to 16
channels of biological signals at 1,000 samples per second each
(79). Hence, the correlation of the dye curve data obtained
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making use of the Chapman method for calculating the LV
chamber volume practical (69). This method was transported to
the human Cath Lab, where it was also used to calculate rates
of LV wall thickening as an index of local LV wall function.
This index of local myocardial function was related to the
concurrent myocardial perfusion (17), thereby starting to meet
the need to provide the simultaneous measures of local myocardial perfusion and functional demand.
In the process of calibrating the accuracy of the method,
several ellipsoidal phantoms and LV chamber casts were used.
Two problems became apparent as the calculated volume was
not accurate (70), and this could not now be attributed to the
measurement shortcuts needed to overcome the bothersome
logistics of manual analysis. First, the method used the X-ray
silhouette; hence true diameters of even a sphere could not be
measured due to the cone geometry of the X-ray beam. Second,
there was ambiguity in the measurement in that, even with
biplane images, identical silhouette diameters would be obtained for a large family of cross-sectional shapes. This was
demonstrated by rotating the phantoms in the X-ray field of
view, which resulted in different calculated volumes, depending on the angle of view. Nonetheless, by using many angles of
view, this variability greatly decreased (107). It was also noted
that video densitometry of the total opacity within the confines
of the silhouette of the LV chamber showed that this was
proportional to the chamber cross-sectional area and was independent of the angle of view (85). Unfortunately, this would
be valid only if the concentration of contrast agent in the
cardiac chamber was uniformly distributed over the duration of
at least one cardiac cycle. Clearly, the solution was rapid
digitization and digital storage of video image data. For this,
the Biomation Corp. (Cupertina, CA) 8100 Transient Recorder
(a programmable digital oscilloscope) that could be used as an
analog-to-digital converter and the Ramtek Corp. (Palo Alto,
CA) solid-state digital memory (developed for video games)
were identified by Dr. Steven Johnson in the laboratory as a
way to achieve this goal.
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Fig. 13. Left bottom panel is the computer-generated image of the first
tomographic reconstruction of an isolated canine LV generated in Earl Wood’s
laboratory. The right top panel shows a photograph of the transmission X-ray
image of that same physical cross section. The labels are by Earl Wood.
Jean Frank, Earl Wood’s secretary, was thumbing through a
throw-away journal to come across a picture that looked
familiar to what “boys in the back room” were talking about in
that it had a schematic of the electron microscope data collection method used for doing a tomographic reconstruction of a
virus tail (15) using multiangle density profiles. This led to
identifying Dr. Gabor T. Herman, a mathematician at State
Fig. 14. First tomographic images at the midventricular level of an anesthetized
dog during passage of contrast agent through the LV. Note the change in
chamber cross-sectional area throughout the cardiac cycle.
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Fig. 12. Photograph of a video screen biplane videofluoroscopic image with
opacified LV chamber outlined by the videometry system. As the TV image
consists of a stack of the 250 horizontal scan lines repeated every 1/60th s,
the location of the brightened spots on each scan line was used to compute
the diameter of the chamber in each of the two orthogonal biplane views.
These diameters are assumed to be the major and minor diameters of an
elliptical cross section and thus can be used to compute the volume of the LV
chamber in that thin cross section. Those values for all of the cross sections of
the LV chamber are summed to get an estimate of chamber volume. This value
could be calculated for each 1/60th s throughout the opacification period.
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Fig. 15. Left panel is a photograph of the
centrifuge being removed from the Medical
Sciences Building, and the right panel is a
photograph of the dynamic spatial reconstructor (DSR) gantry entering the building.
Earl Wood had hoped that the centrifuge
would find a home in the Smithsonian, but
that did not occur, and it was eventually cut
up for scrap (as was the DSR scanner 20
years later). [Reprinted from Wood (94) with
permission.]
Epoch 4 (1976 –1982)
Figure 15 shows the removal of the centrifuge and its
replacement with the DSR gantry in the Medical Sciences
Building, a bittersweet moment for Earl Wood. The DSR was
delivered in late 1979, but it took more than a year’s effort by
engineers Christopher Hansen and James Kinsey to get it going
properly. A detailed description of the DSR and its initial
results is provided in a monograph (68).
Figure 16 shows that the DSR images produced accurate dye
dilution curves, in this case compared with a catheter tip
thermodilution catheter system, which does not suffer from the
blurring of a blood-drawn dilution curve (21). Figure 17 shows
that the presence and functional impact of an atrial septal
defect could be readily demonstrated with the dilution curves
obtained in the right atrium (RA) and LA following an RA
injection of a bolus of contrast agent. This marked a major
improvement in specificity and sensitivity relative to the
blurred indicator dilution curves obtained with catheter-sampled indicator dilution curves obtained in the 1950s (Fig. 8).
Figure 18 shows that the DSR could obtain concurrent dye
dilution-based data, such as myocardial perfusion, chamber
volume, as well as myocardial volume, which is the concurrent, accurate, dynamic structure information that Earl Wood
was aiming for several decades before. Other similar applications to renal physiology (46), lung perfusion and ventilation
(36), and gastrointestinal tract transport (51), as well as collateral development of software (72) and other instrumental
augmentations (44), resulted. The last use of DSR scan data in
a scientific publication was in 2003 (20). Among the several
unforeseen outcomes of the DSR development, good examples
include the first demonstration of nonselective coronary angiography and dynamic cardiac anatomy without the need for
ECG gating.
As T. S. Eliot said, “We shall not cease from exploration,
and at the end of all our exploring will be to arrive where we
started and know the place for the first time” (19). Earl Wood’s
dream had come true: the demonstration of the power of the
accurate indicator dilution curve, the ability to sample any
location within an organ without the need for a sampling
catheter, and the ability to relate those curves to other concurrent biomedical signals, as well as dynamic anatomy, so that
supply and demand of organ function could be quantified.
DISCUSSION
One striking feature of Earl Wood’s career was the
multidisciplinary nature of his laboratory (42). Another
Fig. 16. Comparison of the close match of timing and
shape of the DSR image-based and thermodilution catheter-based dye dilution curves obtained in the same
anatomic location at the same time. [Reprinted from Liu
et al. (57) with permission.]
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University in Buffalo, who provided an Algebraic Reconstruction Technique algorithm, which could be used to do the
tomographic reconstruction for each cross section of the object
imaged at each of the video raster lines. Later he identified the
fan beam filtered back-projection approach as being preferable
in terms of speed of operation (35). On groundhog day, 1973,
the X-ray fluoroscopic imaging system, heart rotation, and
videofluoroscopic image recording systems were integrated to
allow the laboratory’s first tomographic reconstruction of an
isolated heart. Figure 13 shows the reconstruction and an X-ray
projection through the physical slice at that same location.
Although Earl Wood was in London on a year’s sabbatical, he
kept close track of goings on. Not long after, a scan of an
anesthetized dog was made, which demonstrated that timevarying multislice CT images could be generated during injection of contrast agent (Fig. 14). Thus it was now clear as to
what to do, and the design of the dynamic spatial reconstructor
(DSR) scanner resulted. It involved multiple X-ray sources,
each with its opposing detector imager. After several years of
multiple NIH grant submissions, the fabrication of the scanner
was funded in late 1976.
Synthesis Review
E. H. Wood’s Novel Instruments for Exploiting Dye Dilution
Fig. 17. DSR based dilution curves of a dog with a surgically induced atrial
septal defect (ASD) showing the reappearance of the dilution curve in the right
atrium at the same time that the LA curve occurred, diagnostic of the ASD.
Ritman EL
953
biomedical journals) combined to limit the timely dissemination of many of those developments.
Earl Wood’s approach was that one should not speculate,
just uncover the “facts”. Nonetheless, he was not afraid to be
shown that his direction was either wrong (e.g., that the
videometer did not provide the increased accuracy it was
supposed to provide) or at least inferior to other approaches
[e.g., his early work with catheter-tip sensors for recording dye
dilution curves (62) involved much more invasion and restricted sampling locations vs. video densitometry]. Clearly, he
was an early advocate of the more recent mantra of “creative
destruction” (74).
Earl Wood’s research and development were driven by
leveraging indicator dilution techniques, rather than just perfection of a particular class of instruments. This approach has
a life of its own. For instance, after his retirement, the development of the digital X-ray imaging system developed for the
DSR scanner and the tomographic image reconstruction algorithms were the basis for implementing a custom-made micro-CT scanner in the early 1990s with National Science
Foundation funding (43). This scanner enabled pursuit of
questions of cardiovascular structure and function not answerable with the DSR because of its inadequate resolution [e.g., of
arterioles (110)] and the new capability micro-CT provided for
evaluating transmural solute transient in the coronary arterial
wall (29). A future possibility is the use of spectral CT [i.e., in
which the number of X-ray photons within a series of contiguous, narrow photon energy spectra (34) are used to perform
the tomographic image reconstruction] opens the possibility of
dual-indicator dilution techniques by distinguishing the two
indicators by virtue of labeling them with elements of different
X-ray Kedge absorption properties (e.g., gadolinium 50 keV
and iodine 30 keV) instead of the traditional catheter sampled
(56) or external counting (67) radiolabeling techniques. Using
this approach, quantitation of vascular endothelial permeability, with the additional attribute that its spatial distribution at
diverse locations within organ tissue can be established, should
become a reality.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
Fig. 18. Top panels show computer-generated displays of DSR-generated images of
the LV myocardium, chambers, and a regional opacification of perfused myocardium. The bottom panels demonstrate the
accuracy of cardiac structure (myocardial
and chamber volume) and function (myocardial perfusion) parameters obtained with the
DSR. [Reprinted from Robb (71) (top left),
Hoffman and Heffernan (37) (top middle),
Koiwa et al. (48) (top right), Iwasaki et al.
(39) (bottom left), Hoffman and Ritman (38)
(bottom middle), and Wang et al. (88) (bottom right) with permission.]
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issue is to get the funding for a project to which one doesn’t
necessarily know the outcome, and there is no clear mechanistic hypothesis to present. NIH’s National Institute of
Biomedical Imaging and Bioengineering, instituted in the
1990s, was in part an attempt to overcome this traditional
hurdle to instrument development, but this occurred well
after the close of his research career. The mechanistic
hypothesis-driven project generally is successful in either
supporting or refuting such hypotheses. However, it is
generally not a clear end point of instrument development,
which has at best the purpose of providing a more precise or
new measurement capability, which allows crossing a measurement threshold that either destroys or confirms current
understanding. The faith that novel capabilities will lead to
new insights can be a compelling, but tenuous, rationale. If
there is one theme in Earl Wood’s research career, it is that
novel instruments lead to new ideas and to new instrumentation, much as is so well conveyed in Galison’s book (26)
about the development of instruments for the detection and
characterization of the charge, mass, energy, and velocity of
the increasing array of subatomic particles.
Mayo’s reluctance to patent intellectual property until well
into the 1990s resulted in much of the software and hardware
developed by Earl Wood’s research group not being patented
and the delayed publications (due to “too busy” and difficulty
to publish nonhypothesis-driven work to be published in major
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E. H. Wood’s Novel Instruments for Exploiting Dye Dilution
AUTHOR CONTRIBUTIONS
Author contributions: E.L.R. interpreted results of experiments; E.L.R.
drafted manuscript; E.L.R. edited and revised manuscript; E.L.R. approved
final version of manuscript.
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Ritman EL
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6. Brown GE Jr., Pollack AA, Clagett OT, Wood EH. Intra-arterial blood
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13. Coulam CM, Greenleaf JF, Tsakiris AG, Wood EH. Three-dimensional computerized display of physiologic models and data. Comput
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14. Crehan EL, Kennedy RLJ, Wood EH. A study of the oxygen saturation of arterial blood of normal newborn infants by means of a modified
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15. Crowther RA. Three dimensional reconstruction and the architecture of
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17. Dumesnil JG, Ritman EL, Davis GD, Gau GT, Rutherford BD, Frye
RL. Regional left ventricular wall dynamics before and after sublingual
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803–806, 1968.
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Explanation. New York: Harcourt, Brace and World, 1961.
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1977.
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dimensions and shape of homogeneous objects from biplane roentgenographic data with particular reference to angiocardiology. Proc San
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Wood EH, Sturm RE, Sanders JJ. Data processing in cardiovascular
physiology with particular reference to roentgen videodensitometry.
Mayo Clin Proc 39: 849 –865, 1964.
Wood EH, Sutterer WF. Improved resistance wire strain-guage manometers adaptable for biologic measurements. J Lab Clin Med 45:
153–158, 1955.
Wu XS, Ewert DL, Liu YH, Ritman EL. In vivo relation of
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supporting microvascular site for autoregulation. Circulation 85:
730 –737, 1992.
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97. Wood EH, Clark DM, Lambert EH. An analysis of factors involved in
the protection afforded man by pneumatic anti-blackout suits (Abstract).
Fed Proc 4: 79, 1945.
98. Wood EH, Code CF. The physiologic basis of volunteer (self-protective) maneuvers capable of increasing man’s tolerance of positive acceleration. In: Abstracts of the XVII International Physiology Congress.
Oxford, UK, 1947.
99. Wood EH, Collins DA, Moe GK. Electrolyte and water exchanges
between mammalian muscle and blood in relation to activity. Am J
Physiol 128: 635–652, 1940.
100. Wood EH, Geraci JE. Photoelectric determination of arterial oxygen
saturation in man. J Lab Clin Med 34: 387–401, 1949.
101. Wood EH, Hepper RL, Weidmann S. Inotropic effects of electric
currents. I. Positive and negative effects of constant electric currents or
current pulses applied during cardiac action potentials. II. Hypothesis:
calcium movements, excitation-contraction coupling and inotropic effects. Circ Res 24: 409 –445, 1969.
102. Wood EH, Knutson JRB, Taylor BE. Measurement of blood content
and arterial pressure in the human ear. Proc Staff Meet Mayo Clin 25:
398 –405, 1950.
103. Wood EH, Lindberg EH, Baldes EJ, Cole CF. Effects of acceleration
in relation to aviation. Fed Proc 3: 327–344, 1946.
104. Wood EH, Lindberg EF, Code CF, Baldes EJ. Effect of partial
immersion in water on response of healthy men to headward acceleration.
J Appl Physiol 18: 1171–1179, 1963.
105. Wood EH, Nolan AC, Donald DE, Edmundowicz AC, Marshall HW.
Technics for measurement of intrapleural and pericardial pressures in
•