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Contemporary Reviews in Cardiovascular Medicine
Myocardial Energetics and Efficiency
Current Status of the Noninvasive Approach
Paul Knaapen, MD, PhD; Tjeerd Germans, MD; Juhani Knuuti, MD, PhD;
Walter J. Paulus, MD, PhD; Pieter A. Dijkmans, MD; Cornelis P. Allaart, MD, PhD;
Adriaan A. Lammertsma, PhD; Frans C. Visser, MD, PhD
T
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he heart is an aerobic organ that relies almost exclusively on
the aerobic oxidation of substrates for generation of energy.
Consequently, there is close coupling between myocardial oxygen consumption (MV̇O2) and the main determinants of systolic
function: heart rate, contractile state, and wall stress.1 As in any
mechanical pump, only part of the energy invested is converted
to external power. In the case of the heart, the ratio of useful
energy produced (ie, stroke work [SW]) to oxygen consumed is
defined as mechanical efficiency, as originally proposed by Bing
et al.2 Under normal conditions this ratio is ⬇25%, and the
residual energy mainly dissipates as heat.3 In pathophysiological
disease states, such as heart failure, mechanical efficiency is
reduced, and it has been hypothesized that the increased energy
expenditure relative to work contributes to progression of the
disease.4,5 Moreover, therapeutic interventions that enhance
mechanical efficiency have proven to be beneficial with respect
to outcome.6 It is therefore desirable to quantify efficiency of the
heart to study disease processes and monitor interventions.
Both cardiac oxidative metabolism and mechanical work,
and thus efficiency, can be quantified through invasive
measurements. Although these measurements are accurate
and currently considered the gold standard, in clinical practice they are limited because of the need for dual-sided heart
catheterization and selective catheterization of the coronary
sinus. Recent advances in imaging techniques, however, offer
the possibility to noninvasively estimate MV̇O2 and mechanical work by positron emission tomography and echocardiography or by magnetic resonance imaging, respectively.
This review discusses the principles of mechanical efficiency, together with its invasive and noninvasive assessment, as well as their strengths and pitfalls. Finally, results
from clinical pathophysiological studies are discussed.
Blood flow can be estimated with the use of thermodilution or
Doppler (electromagnetic flowmeter) methods after accessing
the coronary sinus through right-sided heart catheterization.
As oxygen dissolved in blood is negligible and hemoglobin
concentrations in arterial and venous blood are similar,
arteriovenous oxygen content difference can be obtained by
determination of the differences in oxygen saturation levels
between arterial and coronary sinus blood. This method to
determine oxygen utilization is currently considered the gold
standard, although it should be noted that it is limited by its
invasive nature, susceptibility to sampling errors, and the fact
that only global MV̇O2 can be assessed, which also includes
oxidative metabolism of the right ventricle and both atria.
Furthermore, thebesian left ventricular (LV) flow (⬇1% to
2% of total coronary flow) is unaccounted for, and an
additional noninvasive estimate of LV mass is required to
calculate oxidative metabolism per gram of tissue.
Output energy is defined as force · displacement and is
expressed in joules (J). Energy generated by the heart can be
divided into actual produced energy (ie, external work [EW]
or SW) and potential energy.3 These parameters can best be
estimated by generation of a pressure–volume (PV) loop of
the cardiac cycle by use a conductance catheter placed in the
left ventricle (Figure 1A). EW is defined by the area contained within the PV-loop. Potential energy can subsequently
be estimated when a family of PV loops is acquired during
different loading conditions, eg, by transient vena cava
occlusion (Figure 1B). Connection of the end-systolic and
end-diastolic points in the PV loops gives the end-systolic
and end-diastolic PV relations, respectively. The slopes of
these relations in turn function as indices of LV contractility
and stiffness, respectively (Figure 1C). The area under the
curve on the left side of EW and confined by the slopes of the
end-systolic pressure–volume relation and the end-diastolic
pressure–volume relation represents potential energy. The
total pressure–volume area (PVA) (ie, the sum of EW and
potential energy) equals total mechanical energy generated by
the heart per beat.3
Invasive Measurement of Mechanical Efficiency
To calculate the efficiency of the heart, input and output
energy must be obtained. The first can be derived from MV̇O2
(mL O2 · min⫺1) measurements according to the Fickprinciple by multiplying coronary sinus blood flow (mL ·
min⫺1) by the arteriovenous oxygen content difference.7
From the Department of Cardiology (P.K., T.G., P.A.D., C.P.A., F.C.V.), the Laboratory of Physiology (W.J.P.), and the Department of Nuclear
Medicine & PET Research (A.A.L.), VU University Medical Center, Institute for Cardiovascular Research, Amsterdam, The Netherlands, and the Turku
PET Center (J.K.), University of Turku, Turku, Finland.
Correspondence to Dr Paul Knaapen, Department of Cardiology, 6D 120, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam,
The Netherlands. E-mail [email protected]
(Circulation. 2007;115:918-927.)
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.660639
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Figure 1. A, Schematic graphic of a pressure–volume loop. With each heart beat a full loop is described. At end-diastole, isovolumic
contraction occurs. When the aortic valve opens, ejection begins and during the ejection phase volume decreases, whereas pressure
changes relatively little. After aortic valve closure, isovolumic relaxation takes place, characterized by a swift pressure drop. When the
mitral valve opens, the chamber begins to fill, and volume increases with a very small increase in left ventricular pressure until the enddiastolic volume is reached. The area contained within the loop is external work (EW). B, A family of PV-loops under different loading
conditions reveals the end-systolic pressure–volume relation (ESPVR) and the end-diastolic pressure–volume relation (EDPVR). C, The
area on the left side of the PV-loop and confined by the ESPVR and EDPVR represents potential energy (PE). EW and PE together
(pressure–volume area, PVA) represent total generated mechanical energy. D, Noninvasive estimate of the PV-loop based on stroke
volume and end-systolic pressure estimation results in a rectangle. Areas of under- and overestimation compared with the original
PV-loop are indicated. E, Diastolic dysfunction is characterized by an augmented pressure rise during the diastolic filling phase. F,
Mitral regurgitation markedly influences the isovolumic contraction and ejection period characteristics of the PV-loop.
It is important to realize that 2 stages can be distinguished in
the process of MV̇O2 conversion to mechanical energy: (1)
efficiency of energy transfer from MV̇O2 to total PVA-area and
(2) efficiency of energy transfer from PVA area to EW. The
product of the 2 stages yields the mechanical external efficiency
and is most commonly used in clinical studies as it represents the
conversion of MV̇O2 to “useful” EW. For the sake of clarity and
brevity, only (noninvasive) assessment of mechanical external
efficiency will be discussed in this review.
To express efficiency in a dimensionless value or percentage, MV̇O2 and EW must be converted from units of mL O2
and mm Hg · mL, respectively, to units of energy (J). The
caloric equivalent of 1 mL of O2 is ⬇20 J, whereas 1 mm Hg
· mL equals 1.33 · 10⫺4 J.8 Figure 2 schematically illustrates
the myocardial energy conversion process. Invasive studies in
normal controls have demonstrated that ⬇25% of consumed
oxygen is finally converted to external work.2,9,10 The residual energy is used for nonmechanical activity of basal
metabolism and excitation-contraction coupling, although the
majority is converted to heat.3,11
Noninvasive Measurement of
Mechanical Efficiency
Input Energy, Oxidative Metabolism
Noninvasive assessment of MV̇O2 is currently limited to
positron emission tomography.12 Two MV̇O2 tracers have
been developed: carbon-11–labeled acetate (11C-acetate)13
Figure 2. Energy flow diagram from O2 consumption to EW. Efficiency from O2 to ATP and PVA are
⬇60% to 70%. Efficiency transfer from PVA to EW
depends on contractile function and loading conditions. EC indicates excitation contraction coupling;
BM, basal metabolism. Adapted from Suga.3 Used
with permission of the publisher. Copyright ©
1990, the American Physiological Society.
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Figure 3. Oxidative metabolism in myocardium. Oxidative phosphorylation is characterized by transferal of electrons to oxygen,
producing water (H2O) in the final step, and is virtually the only
source of ATP production in the human heart. Nicotinamide
adenine dinucleotide (NADH⫹H⫹) and flavin adenine dinucleotide (FADH2), which are produced by glycolysis, beta-oxidation,
and oxidation of acetyl-coenzyme A in the TCA cycle, act as
carriers of these electrons. The TCA cycle flux is tightly coupled
with oxidative phosphorylation and can therefore be used to
estimate overall oxidative metabolism. 11C-acetate is rapidly
converted to acetyl-coenzyme A, and its primary metabolic fate
is via the TCA cycle where the 11C-activity is predominantly
transported to 11CO2. The rate of 11CO2 efflux is directly correlated to the TCA cycle flux, which makes 11C-acetate suitable as
a tracer to measure MV̇O2. Alternatively, because it is the final
electron acceptor in all pathways of aerobic metabolism, 15O2
can be used as a MVO2 tracer. Fp indicates flavoprotein; Q,
coenzyme. Reprinted from Klein et al,13 with kind permission of
the publisher. Copyright © 2001, Springer Science and Business Media.
and oxygen-15–labeled molecular oxygen (15O2).14,15 As
shown in detail in Figure 3, acetate is a 2-carbon chain free
fatty acid, which is taken up by the heart and subsequently
rapidly converted to acetyl-coenzyme A in the mitochondrial
matrix. The primary metabolic fate of acetyl-coenzyme A is
via the tricarboxylic acid (TCA) cycle , where 11C-activity is
transported to carbon-11–labeled carbon dioxide (11CO2),
which readily diffuses from myocardial tissue.13,16 Figure 4
shows an example of a dynamic cardiac 11C-acetate positron
emission tomography acquisition and its corresponding myocardial time–activity curve. Within a few minutes after
intravenous injection, tracer activity in myocardium reaches a
maximum level that is directly proportional to myocardial
blood flow. Thereafter, activity is cleared in a biexponential
fashion, and the rate constants k1 and k2 can be assessed
through curve fitting. The rapid phase, k1, represents the
efflux of 11CO2 produced by the TCA cycle. Because of the
tight coupling between the TCA cycle and oxidative phosphorylation, k1 correlates closely with MV̇O2, as has been
demonstrated under a wide range of conditions, and therefore
functions as an index of oxygen use.16 The slow phase, k2,
represents clearance of 11C-activity, which is incorporated
into amino acids and TCA cycle intermediates. This method
of MV̇O2 estimation has been further simplified by monoexponential fitting of the linear part of the time–activity curve
(kmono), which correlates well with k1.16 To reduce the
length of the scanning protocol to ⬍30 minutes, the slow
wash-out phase k2 can be disregarded.
The use of the second available tracer to determine MV̇O2
(ie, 15O2 gas) expands on the well-defined measurements of
myocardial blood flow by use of oxygen-15–labeled water
(H215O).14,15 Inhalation of 15O2 causes 15O2 to bind to
hemoglobin and, after transport to peripheral tissues, 15O2 is
converted by cellular metabolism to H215O.17 A tracer kinetic
model has been developed to account for recirculating H215O,
which allows for oxygen extraction fraction to be estimated
(Figure 5). Additional corrections, however, are required for
substantial spillover effects from radioactivity in adjacent
ventricular blood and lung tissue, which necessitates an
additional blood pool scan with oxygen-15–labeled carbon
monoxide (C15O) and a transmission image to calculate lung
volume. Finally, the combination of a transmission, 15O2,
H215O, and C15O scan, displayed in Figure 6, allows the
Figure 4. Short axis view of a dynamic
11
C-acetate PET acquisition displays
transit of radioactivity through the right
and left ventricular cavity after a bolus
injection. Subsequently, 11C-acetate is
readily taken up by the myocardium and
reaches a maximum after ⬇5 minutes.
The matching myocardial time–activity
curve demonstrates the bi- and monoexponential curve fitting of the wash-out
phase of activity. The slope of the fitting
curves k1 and kmono are correlated to
MV̇O2.
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Noninvasive Assessment of Myocardial Efficiency
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Figure 5. Simplified schematic representation of the compartment model to measure oxygen extraction fraction and MV̇O2 by use of
PET and 15O2 inhalation. The defined region of interest (ROI) comprises radioactivity in the myocardial tissue as well as spillover activity
from the LV cavity blood pool and lung. Spillover corrections can be made with the use of LV blood pool and lung volume imaging with
C15O and a transmission image, respectively, as depicted in Figure 6. Hemoglobin-bound 15O2 is extracted from the intravascular
space to the tissue space (myocardium) where it is instantaneously converted into H215O. The latter is freely diffusable across the capillary membrane and is washed out in proportion to myocardial blood flow. Therefore, shortly after 15O2 inhalation is started, radiolabeled
water that is recirculating must be corrected for to measure the oxygen extraction fraction. This requires arterial blood sampling to
determine the relative contribution of 15O2 and H215O to total arterial radioactivity. Alternatively, in steady-state conditions during continuous inhalation of 15O2, the proportion of recirculating H215O to total arterial radioactivity has been shown to be relatively constant at
⬇18% and can therefore be fixed in the compartment model, which obviates the need for arterial blood sampling.17 Finally, a separate
H215O scan is performed to measure myocardial blood flow. MV̇O2 equals the product of oxygen extraction fraction, myocardial blood
flow, and the oxygen content of blood. MBF indicates myocardial blood flow; OEF, oxygen extraction fraction. Adapted from Iida et al14
with permission of the publisher. Copyright © 1996, the American Heart Association.
quantification of both myocardial blood flow and oxygen extraction fraction. Subsequently, by multiplying arterial oxygen
content of blood with myocardial blood flow and oxygen
extraction fraction, MV̇O2 can be expressed in absolute terms per
gram of myocardial tissue (mL O2 · g⫺1 · min⫺1).
Output Energy, External Mechanical Work
In contrast to oxidative metabolism, noninvasive assessment of mechanical EW is relatively straightforward. To
estimate the area contained within the PV-loop, only
knowledge of stroke volume (SV) (ie, LV end-diastolic
and end-systolic volumes and end-systolic LV pressure
[LV-Pes]) is required. LV volumes can routinely be
derived by various imaging techniques, which include
magnetic resonance imaging, echocardiography, and nuclear imaging.18 LV-Pes roughly corresponds to the mean
arterial blood pressure of the brachial artery and can be
assessed by a simple sphygmomanometer.19 The product of
mean arterial blood pressure and SV yields a fairly
accurate estimate of EW (Figure 1D).
Figure 6. Examples of a transmission
(Tx), steady state oxygen (15O2), and
blood pool (15CO) image obtained by
positron emission tomography in a transaxial view. Through a weighted subtraction technique, lung volume and ventricular blood pool are subtracted from the
15
O2 image. The lower panel, 15O2-myo,
visualizes the myocardial 15O2 activity
that can be used to calculate the oxygen
extraction fraction. Courtesy of H. Laine,
Turku PET Center, Turku, Finland.
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Mechanical Efficiency
The combination of the noninvasive estimates of MV̇O2 and
EW as described above allows for the assessment of mechanical efficiency according to the equation below,20
Efficiency⫽
MAP 䡠 SV 䡠 HR 䡠 1.33 䡠 10⫺4
MV̇O2 䡠 LVM 䡠 20
where HR is heart rate and LV mass (LVM) is measured in
grams, the conversion factors to joules are as mentioned
earlier. It needs to be emphasized that in this equation MV̇O2
is expressed in absolute terms. The most commonly employed method to estimate oxidative metabolism noninvasively, however, remains the exponentional curve-fitting
procedure of 11C-acetate, which yields an index of MV̇O2.
Therefore, Beanlands et al21 introduced an alternative efficiency index, the so called work metabolic index (WMI):
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WMI⫽
SBP 䡠 SVI 䡠 HR
(mm Hg 䡠 mL 䡠 m⫺2)
clearance rate of 11C-acetate
where SVI is stroke volume index and SBP is systolic blood
pressure. This equation is a modification of the minute
work-to-oxygen consumption relationship originally defined
as mechanical efficiency by Bing et al.2 Traditionally, systolic blood pressure instead of mean arterial blood pressure is
used to calculate the work metabolic index, although this is
based solely on the personal preferences of the investigators
who first proposed this index and is of little clinical
significance.21
Strengths and Limitations of the
Noninvasive Approach
Oxidative Metabolism
Despite the fact that myocardial turnover of 11C-acetate is
most commonly used to noninvasively assess MV̇O2, it has
several limitations.12 First and most important, only a semiquantitative index of oxidative metabolism is obtained. Even
though databases exist from animal experiments and studies
in humans to convert the clearance rate constants (units ·
min⫺1) to equivalents of absolute units (mL · g⫺1 · min⫺1), the
relationships found in those relatively small studies, which
were performed under predominantly normal physiological
conditions, may not hold true in a variety of pathological
disease states. Second, the metabolic fate of 11C-acetate
depends, at least in part, on pathological conditions such as
ischemia and hibernation.16,22 In such conditions the initial
myocardial 11C-acetate clearance rate k1 or kmono slightly
overestimates actual MV̇O2 because of alterations in the TCA
amino acid pool sizes. Third, fluctuations in the arterial input
curve of tracer activity and spillover artifacts caused by
alterations in cardiac output and recirculation of 11C-activity,
respectively, can significantly affect tracer kinetics that are
unrelated to oxygen utilization.23,24 Finally, selection of data
points from the time–activity curve for subsequent analysis is
susceptible to observer variability. To circumvent some of
these drawbacks, compartment modeling approaches for
myocardial 11C-acetate kinetics have been developed.13,24 The
essence of these approaches lies in the correction of the
arterial input curve of 11C-acetate for contaminating metabo-
lites, predominantly 11CO2. The major advantage of this
modeling approach is the fact that MV̇O2 is quantified in
absolute terms. Furthermore, variability of the input curve
and spillover artifacts are taken into account. However, the
need for arterial cannulation, repetitive sampling of arterial
blood to measure radiolabeled metabolites, and its subsequent
implementation in the modeling procedure make this method
cumbersome. In addition, corrections for the partial volume
effect (underestimation of true radiotracer concentrations that
is based on cardiac dimensions and motion) need to be carried
out. As these corrections themselves may induce errors in the
estimation of absolute MV̇O2, many groups return to the
simple, but robust semiquantitative monoexponential or biexponential curve fitting method.
15
O2 is theoretically the most suitable tracer to assess
oxidative metabolism, as oxygen is the final electron acceptor
in all pathways of aerobic metabolism. This approach is
independent of cellular metabolic changes that occur in
pathological conditions and conveys absolute values of
MV̇O2. Unfortunately, only a few centers worldwide are
currently equipped to perform the combination of these
specific 15O-scans, and the multiple tracer usage makes this
method prone to motion artifacts. In addition, the data
analysis, which includes the modeling procedure, is very
challenging, and it has been applied only in small series of
subjects. Nevertheless, it should be considered the gold
standard for noninvasive quantification of MV̇O2.
Regardless of the methodology used to assess MV̇O2,
substrate metabolism affects the ratio of adenosine triphosphate (ATP) produced per oxygen molecule consumed. From
Figure 3, one can calculate this ratio for various substrates
and conclude that glucose metabolism yields 11% to 13%
more ATP per unit of oxygen consumption compared with
free fatty acid metabolism, irrespective of cardiac workload.13,25 Therefore, substrate metabolism affects mechanical
efficiency and metabolic standardization (ie, during a fasting
state, it is required when these measurements are performed).
External Mechanical Work
Although external mechanical work calculation derived from
SV and mean arterial blood pressure is elegant in its simplicity, some inaccuracies of this approach should be mentioned.
First, the original PV-loop is represented as a rectangle,
which results in some overestimation by including the area
under the curve of the diastolic filling phase. Especially in
patients with diastolic dysfunction, this effect can be substantial (Figure 1E). Furthermore, the parabolic shape of the
systolic ejection phase of the loop is disregarded, which may
result in over- or underestimation, depending on the characteristics of the individual PV-loop. Second, valvular disease
significantly hampers noninvasive estimates of EW. In aortic
stenosis, the systolic transvalvular pressure gradient results in
underestimation of LV-Pes measured by a sphygmomanometer. Echocardiography-derived transvalvular pressure gradient estimation, however, can accurately correct for this
underestimation.26 More complex are the discrepancies
caused by mitral regurgitation. The systolic bidirectional flow
of blood into the left atrium and aorta causes the isovolumic
contraction phase to be shortened. For a given SV, this
Knaapen et al
Noninvasive Assessment of Myocardial Efficiency
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markedly diminishes EW by regurgitation of blood into the
low-pressure atrium. Noninvasive assessment of EW will
therefore be overestimated in proportion to the magnitude of
regurgitating volume (Figure 1F). This problem can partly be
resolved by substitution of total with forward SV determined
by aortic flow measurements derived by echocardiography27
or magnetic resonance imaging.28 The subsequent calculation
of the so-called forward SW, however, may not accurately
reflect actual SW in these patients. Mitral regurgitation,
therefore, remains an important source of error in noninvasive
quantification of EW.
A more general disadvantage lies in the fact that LV
volumes are usually derived by echocardiography, which is
hampered by a poor ultrasound window in a fairly large
percentage of patients.18 Furthermore, geometric assumptions, made when 1- or 2-dimensional echocardiography is
used, can lead to substantial inaccuracies in patients with, for
example, severe LV remodeling and/or aneurysms. Magnetic
resonance imaging overcomes these limitations but is less
widely available, is contraindicated in patients with implanted
devices, and ideally requires a regular heart beat for gating
purposes, which excludes a reliable assessment in the presence of arrhythmias. More recently, 3-dimensional echocardiography has also proven to overcome some of the aforementioned limitations,29 particularly when images are
enhanced with the use of contrast agents.30
Mechanical Efficiency
Table 1 lists results of efficiency studies in healthy controls.
A few remarks are in order. The noninvasively obtained
mechanical efficiency values are somewhat lower than those
found with invasive methods. This discrepancy is probably
related to differences in loading conditions and contractile
state, which affect mechanical efficiency,3 in combination
with methodological issues as already discussed. It should be
further noted that the number of both invasive2,9,10 and
noninvasive20,31–35 studies in normal physiology is rather
small and the accuracy and reproducibility of efficiency
measurements have not yet been adequately demonstrated.
Although validation studies are available for the assessment
of noninvasive oxidative metabolism and external mechanical
work separately, validation studies of noninvasive versus
invasive efficiency estimation in human subjects are lacking.
Clearly, more studies are warranted to more reliably define
TABLE 1.
normal limits and reproducibility of mechanical efficiency in
humans.
Of interest, the noninvasive approach surpasses the invasive method in its unique possibility to quantify myocardial
efficiency at a regional level, which is of specific relevance in
coronary artery disease and cardiomyopathies that display
marked regional disease expression as can be appreciated in
the clinical studies described in the next section. Various
noninvasively determined regional work parameters, which
are based on regional wall stress estimation, systolic wall
thickening, and myocardial deformation that can be related to
regional oxidative metabolism, have been proposed (Figure
7).36 –38
A final pitfall that must be addressed is the dual-imaging
approach in the quantification of efficiency, which is confounded by potential discrepancies in hemodynamic conditions between imaging sessions. Moreover, particularly in
regional efficiency assessment, accurate alignment of myocardial segments must be ensured. Coregistration software for
image-fusion during postprocessing may be of use, but
dual-imaging tools will ultimately be required to optimize
regional alignment and simultaneous assessment of metabolism and function.
Clinical Studies in Cardiovascular Disease
Coronary Artery Disease
Coronary artery disease is the most common cause of
compromised myocardial perfusion. The accompanying limited supply of oxygen frequently results in ischemia, which in
turn causes a rapid decline in ATP production and immediately induces contractile dysfunction.1 In the acute phase of
ischemia, therefore, reduction in MV̇O2 and contractile function are matched. After a transient period of ischemia, when
oxygen delivery has already been restored, however, prolonged reversible contractile dysfunction can be observed
without signs of cellular necrosis. This condition is referred to
as myocardial stunning.39 Gerber et al38 and Barnes and
colleagues40 showed that oxidative metabolism of stunned
myocardium exhibited a slight and nonsignificant reduction
compared with baseline values and remote myocardium,
which seemed to parallel levels of perfusion. Regional
oxygen use in stunned myocardium, however, was relatively
high compared with contractile function, which yielded a
marked (transient) reduction of mechanical efficiency. As a
Mechanical Efficiency Studies in Normal Controls
Study
Year
No.
Method
PET Tracer
ME
Bing et al2
1949
4
Invasive
䡠䡠䡠
22⫾2
Nichols et al10
1986
8
Invasive
䡠䡠䡠
29⫾6
Arnoult et al9
1997
11
Invasive
Vanoverschelde et al31
1993
8
Noninvasive
䡠䡠䡠
11
C-acetate
35⫾6
Porenta et al20
1999
11
Noninvasive
32
923
11
C-acetate
26⫾6
16⫾6
Takala et al
1999
11
Noninvasive
15
Laine et al33
1999
10
Noninvasive
15
Akinboboye et al34
2004
10
Noninvasive
11
C-acetate
16⫾3
Peterson et al35
2004
12
Noninvasive
11
C-acetate
19⫾7
O2
14⫾4
O2
18⫾4
ME indicates mechanical efficiency (% ⫾ SD); PET, positron emission tomography.
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A
C
E
B
D
F
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Figure 7. End-diastolic (upper panels) and end-systolic (lower panels) cine (A to D) and tagging (E to F) magnetic resonance images in
a short axis view of a patient with a previous myocardial infarction of the anterior wall. Endocardial and epicardial borders can be delineated to allow accurate estimation of wall thickness. In combination with measurements of LV diameter and end-systolic pressure,
regional wall stress can be calculated in absolute terms (g · cm⫺2) according to Laplace’s law.36 Relative work parameters can also be
obtained by estimation of regional systolic wall thickening (C and D) and myocardial deformation (E and F).37 The magnetic resonance
imaging tissue tagging technique to quantify systolic deformation alters the magnetic properties of the myocardial tissue for a short
period of time and appears as black lines on the images.37 The relative change between these lines from end-diastole to end-systole
can be quantified in 3 dimensions, and relative deformation (ie, strain) can be calculated (expressed in %). Strain is generally considered a noninvasive parameter of regional contractility. It should be emphasized, however, that systolic wall thickening and strain analysis cannot be used to calculate actual external work and therefore do not allow quantification of mechanical efficiency in absolute
terms.
compensatory mechanism, (post)ischemic myocardium displays a shift from fatty acid to glucose use as the latter yields
11% to 13% more ATP per unit of consumed oxygen.13,25
Augmentation of glycolysis therefore renders the ischemic
heart metabolically, and consequently mechanically, less
inefficient.16,39
Although stunning is, by definition, a reversible condition,
long-term repetitive stunning may eventually result in chronic
progressive contractile dysfunction and transit to a state of
hibernation.41 In the course of such a transitional state, there
is a gradual decline in mechanical efficiency as oxidative
metabolism remains relatively preserved.39,42 Hibernation
requires rapid revascularization to avoid irreversible damage.
Otherwise, oxygen use ultimately falls below a critical
threshold, and dysfunctional myocardium becomes unsalvageable.43,44 Conversely, in cases of timely revascularization, regional contractile function and consequently mechanical efficiency may be restored, which in turn is accompanied
by improved prognosis.45 More recently, metabolic interventions with drugs that increase glucose metabolism in ischemic
heart disease have demonstrated that this energetically more
favorable circumstance also translates into improved systolic
function and improved clinical outcome.46
Dilated Cardiomyopathy
Heart failure produced by dilated cardiomyopathy, regardless
of that cardiomyopathy’s cause, is characterized by an unfavorable mechanoenergetic profile (ie, diminished mechanical
efficiency).47 In an effort to optimize peripheral tissue perfusion, initial pharmacological approaches in heart failure were
primarily designed to instigate an acute enhancement in
systolic performance of the weakened heart muscle with the
use of sympathomimetic agents.4,6 Apart from improving
systolic cardiac performance, however, these agents elevate
heart rate and hence MV̇O2. The effects on mechanical
efficiency, however, are less clear. Positive inotropic agents
like dobutamine increase energetic costs of nonmechanical
work, which is often referred to as the oxygen-wasting
effect.3,31 Furthermore, increased contractility increases oxygen consumption per beat.48 On the other hand, dobutamine
causes a reduction in systemic vascular resistance and thus
LV load, which may offset these increased energetic costs.
Depending on the magnitude of each of these effects, mechanical efficiency may either be increased, decreased, or
unaltered.20,21,31 Regardless of efficiency, the already inefficient and failing heart is forced to further increase its total
energy expenditure, with potential deleterious effects.
Meanwhile, it has become apparent that compensatory
long-term activation of renin-angiotensin and adrenergic
systems results in accelerated disease progression and plays a
central role in the process of ventricular remodeling.6,49
Pharmacological antagonism of the neurohormonal system
with angiotensin-converting enzyme inhibitors and
␤-blockers have a profound beneficial effect on ventricular
mechanics and energetics. Angiotensin-converting enzyme
inhibitors substantially reduce mean aortic pressure and
systemic vascular resistance. Because of the related reduction
in LV load, stroke volume and SW immediately increase
while MV̇O2 is lowered, thereby augmenting mechanical
efficiency.50
Unlike vasodilators and inotropic drugs, ␤-blockers do not
immediately improve hemodynamics of a failing heart. In
contrast, on initiation heart rate decreases, and contractile
function is further depressed, which frequently results in
Knaapen et al
Noninvasive Assessment of Myocardial Efficiency
deterioration of hemodynamics.51 The negative inotropic and
chronotropic properties, however, diminish the energy requirements of the heart. It is of interest that in the ensuing
months of therapy a seemingly paradoxical improvement in
contractile function occurs, whereas oxygen use decreases.
Consequently, mechanical efficiency improves, as has been
demonstrated in invasive52 and noninvasive53 placebocontrolled studies.
tion.61 Recently, Laine et al33 have provided more insight into
the mechanoenergetic effects of hypertrophy. In hypertensive
patients without LV hypertrophy, MV̇O2 was increased in
response to augmented metabolic demand caused by a higher
workload, which leaves efficiency unaltered, although a
nonsignificant reduction was observed. In hypertrophy, however, oxygen utilization per gram of myocardium was normalized and comparable to controls. Total SW did not change
in the presence of hypertrophy, but work delivered per gram
of hypertrophied tissue was disproportionately depressed
relative to the changes observed in MV̇O2. Therefore, the
apparent normalization of oxygen utilization per unit of
weight induced by hypertrophy occurred at the expense of
mechanical efficiency. It should be noted, however, that these
observations could not be reproduced in hypertrophy caused
by aortic valve stenosis62,63 or in patients with hypertensive
eccentric hypertrophy.34 This underscores the complexity of
various adaptive processes that occur in hypertrophy under
different pathological loading conditions. Clearly, more studies in carefully selected subgroups of patients are warranted.
Mechanical Dyssynchrony
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Left bundle-branch block is a common finding in dilated
cardiomyopathy and is associated with poorer prognosis.54
The slow propagation of myocardial depolarization typically
induces mechanical dyssynchrony (ie, contraction of the
interventricular septum and of the lateral free wall occur at
different points in the time of the cardiac cycle). This type of
contraction is characterized by waste of myocardial work as
energy is lost in shifting blood within the heart itself instead
of contributing to ejection.55 Left bundle-branch block therefore renders the already failing heart even more inefficient.
Recently, in an attempt to counteract the detrimental impact
of mechanical dyssynchrony, cardiac resynchronization therapy has emerged as a new treatment for a subgroup of patients
with drug-refractory symptomatic dilated cardiomyopathy
and mechanical dyssynchrony.56 Cardiac resynchronization
therapy restores ventricular synchrony by simultaneously
pacing the interventricular septum and lateral free wall. In
doing so, systolic LV performance is enhanced immediately
(ie, within a few heartbeats after initiation of therapy).57
Moreover, augmented LV work occurs without increasing
energy requirements, thereby inducing a more favorable
mechanoenergetic profile.57,58 Furthermore, the effects on
mechanical efficiency are maintained over time and disappear
immediately on cessation of long-term cardiac resynchronization therapy, which stresses the beat-to-beat therapeutic
effect.59,60
Conclusions and Future Perspectives
An imbalance between oxidative metabolism and cardiac
function appears to be a sensitive marker of myocardial
pathology, albeit rather unspecific. In this respect, impaired
mechanical efficiency may represent a final common pathway in cardiomyopathy, regardless of cause, and provides
important prognostic information. Moreover, as summarized
in Table 2, therapeutic interventions that improve outcome
are associated with restoration of efficiency, which highlights
the clinical significance of this parameter. Although some
shortcomings must be acknowledged, recent advances in
imaging techniques have enabled reliable noninvasive methods to assess efficiency with obvious advantages over invasive methods. In particular, monitoring interventions that
require serial measurements over longer periods of time
should benefit from a noninvasive approach. Evaluation of
new treatment strategies in this manner in a relatively small
number of patients can provide important insight and is an
important step toward testing interventions in large clinical
trials.
Left Ventricular Hypertrophy
When the heart is subjected to high mechanical load, LV
hypertrophy frequently occurs as an adaptive physiological
response to lower wall stress and maintains systolic func-
TABLE 2. Mechanoenergetic Characteristics in Myocardial Pathology and Effects of Interventions
in Humans
Condition
MV̇O2
EW
ME
Intervention
MV̇O2
EW
ME
Ischemia
2
2
7
Stunning
7/2
2
2
䡠䡠䡠
Time
䡠䡠䡠
7
䡠䡠䡠
1
䡠䡠䡠
1
Hibernation/repetitive stunning
7/2
22
22
1
Dilated cardiomyopathy
2
22
925
2
Revascularization
7
1
Metabolic therapy
7
1
1
␤-Agonists
11
1
2
␤-Blockers
2
1
1
Vasodilators
2
1
1
Ventricular dyssynchrony
7
2
2
CRT
7
1
1
Hypertensive concentric LVH
7
2
2
Antihypertensive drugs
NA
NA
NA
EW indicates external work; ME, mechanical efficiency; CRT, cardiac resynchronization therapy; LVH, left ventricular hypertrophy;
and NA, not available. MV̇O2 and EW are adjusted for heart rate and left ventricular mass. Changes are relative to normal controls for
each condition. Chronic changes are reported for interventions and are relative to baseline conditions.
926
Circulation
February 20, 2007
New hybrid imaging tools, such as positron emission
tomography/computed tomography, will provide further improvements through accurate and nearly simultaneous registration of function and metabolism. Furthermore, algorithms
have recently been developed to noninvasively assess both
end-systolic pressure–volume relations64 and end-diastolic
pressure–volume relations.65 These algorithms facilitate
quantification of myocardial contractility and relaxation and
may offer the possibility to estimate the entire PVA noninvasively (Figure 1C). Thereafter, efficiency can be calculated
at different levels of energy transfer (eg, from MVO2 to PVA
and from PVA to EW). Future studies will certainly focus on
development and validation of these promising and clinically
valuable tools.
19.
20.
21.
22.
23.
Disclosures
None.
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KEY WORDS: hemodynamics
䡲
imaging
䡲
metabolism
Myocardial Energetics and Efficiency: Current Status of the Noninvasive Approach
Paul Knaapen, Tjeerd Germans, Juhani Knuuti, Walter J. Paulus, Pieter A. Dijkmans, Cornelis
P. Allaart, Adriaan A. Lammertsma and Frans C. Visser
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Circulation. 2007;115:918-927
doi: 10.1161/CIRCULATIONAHA.106.660639
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