Basic Res Cardiol 93: 1 – 10 (1998)
© Steinkopff Verlag 1998
A. M. Vogt
W. Kübler
Received: 28 July 1997
Returned for revision: 3 September 1997
Revision received: 29 September 1997
Accepted: 3 November 1997
A. M. Vogt · Prof. Dr. W. Kübler (Y)
Medizinische Universitätsklinik
Abteilung Innere Medizin III
Bergheimer Straße 58
D-69115 Heidelberg
Germany
E-mail: Wolfgang_Kuebler@krzmail.krz.uni-
heidelberg.de
ORIGINAL CONTRIBUTION
Heart failure: Is there an energy deficit
contributing to contractile dysfunction?
Abstract Alterations in myocardial
energy metabolism have been demon-
strated in both animal experiments and
clinical observations. Whether these
changes contribute to heart failure has
been a longstanding and controversial
issue.
I. The creatine kinase (CK) system and
the high energy phosphates under phys-
iological conditions and in acute heart
failure:
1. According to in vivo and in vitro
experiments the myocardial crea-
tine/ creatine phosphate (Cr/CP)
system is directly linked to
mitochondrial oxidative phosphory-
lation via the mitochondrial CK.
2. The shift in the mass action ratio of
the CK reaction with increasing
myocardial oxygen consumption
enables marked stimulation of mito-
chondrial respiratory function via
the Cr/CP system with almost main-
tained free energy of the adenosine
triphosphate/adenosine diphosphate
(ATP / ADP) system.
3. In acute heart failure the depressed
myocardial content mainly of CP
can be considered as an adaptive
mechanism related to increased
oxygen demands.
II. The CK system and the high energy
phosphates in chronic heart failure:
1. The alterations observed in the CK
system in chronic heart failure can-
not be interpreted in terms of an
“energy deficit” (i.e., the excess of
what is spent over what is received
on energy).
2. “Energy reserve” (i.e., energy kept
back for future use, to fill an emer-
gency) is markedly reduced in heart
failure.
3. Unter steady state conditions
decreased “energy reserve” cannot
be expected to contribute to heart
failure. Under stress conditions,
however, this mechanism is mani-
fest by reducing contractile reserve.
4. The mechanisms by which
decreased “energy reserve” induces
depression of contractile reserve is
not elucidated.
III. Heart failure related to alterations
in energy metabolism (mitochondrial
diseases, stunned, and hibernating
myocardium):
1. The phenotype of mitochondrial
diseases is predominantly
determined by neurological disor-
ders and myopathies. Therefore, the
patients are rarely referred to a
cardiologist, although the cardiac
involvement may ultimately deter-
mine the patients’ prognosis.
2. Stunned and hibernating myocar-
dium are characterized by prolonged
contractile dysfunction in the
BRC 072
presence of reversibly damaged
myocardium. The underlying
2 Basic Research in Cardiology, Vol. 93, No. 1 (1998)
© Steinkopff Verlag 1998

mechanisms and its triggers are tribute to the progression of the
unknown. disease.
2. As an alternative, however, it can
Interpretations: likewise represent a mechanism to
1. The reduced energy reserve in heart protect the endangered myocardium
failure may be considered to con- from overload.
Key words Heart failure – energy
metabolism – creatine kinase –
adenosine triphosphate – creatine
phosphate

A decreased ATP/ADP ratio, however, not only stimulates

Introduction
Energy deficit in heart failure could arise from increased
myocardial energy demands – such as increased wall stress or
increased muscle mass – or from decreased myocardial energy
supply due to increased intercapillary distance, increased fibro-
sis, increased myocyte diameter, and a decreased mitochon-
drial/myofibrils ratio (35). In order to evaluate the energy status
of the failing heart, the myocardial content of high energy phos-
phates (HEP) was investigated by many groups. Whereas for
adenosine triphosphate (ATP) inconsistent results were
obtained in both human and animal hearts at various stages of
the disease (9, 49, 58, 61, 64), rather consistent decreases in
creatine phosphate (CP) levels were observed (29, 46, 49, 62).
Whether these changes in myocardial energy metabolism con-
tribute to heart failure has been a longstanding and controver-
sial issue (8, 29, 63). CP is synthetised and degraded only via
ATP, therefore, for a given compartment, any change in the
creatine phosphate/creatine (CP/Cr) ratio reflects similar changes
in the ratio of ATP to adenosine diphosphate (ATP/ADP).
The creatine kinase system and the high energy
phosphates under physiological conditions and in acute
heart failure
In acute heart failure, the myocardial contents of high energy
phosphates – mainly of CP and to a much lesser extent of ATP
– are reduced (16, 38, 40). This decrease has been considered
by some authors as cause of myocardial failure (26, 34). An
alternative explanation, however, would be that the reduced
levels of HEP may reflect a mechanism of adaptation to
increased myocardial work load and increased oxygen con-
sumption (37, 38).
Intact cells and tissues employ respiratory control. Cells
oxidize only enough substrate to synthetise the amount of ATP
required for their metabolic activities. Stimulation of a meta-
bolic activity that utilizes ATP, such as muscular contraction,
results in an increased level of ADP. This, in turn, increases the
oxidation rate of metabolic products in the mitochondria.
Myocardial oxygen consumption should, therefore, assumed
to be stimulated by decreased ATP- and mainly by increased
ADP-concentrations.
mitochondrial oxidative phosphorylation but leads in addition
to a reduction of free energy, which depends on the ATP/ADP
ratio*. According to Kammermeier et al. (33) “the low level of
free energy change of ATP-hydrolysis rather than ATP-defi-
ciency – at least under anoxia – can be considered to be one
main causal factor of contractile failure”. Hence, with
increased myocardial work, reduction of the ATP/ADP-ratio
seems necessary for stimulation of mitochondrial oxidative
phosphorylation, but instantly free energy of the ATP/ADP-
system may be reduced despite increased myocardial energy
demands under conditions of a one compartment system.
Fig. 1 shows the relation between CP and myocardial oxy-
gen consumption in the range from 0.5 to 12 ml·100 g–1·min–1
in canine experiments (40). The values obtained in acute
myocardial failure – induced by halothane anesthesia and
acute pressure load by infusion of angiotensin II – are within
normal limits if allowance is made for increased oxygen con-
sumption. The same holds true for ATP-content. Corrected for
the increased myocardial oxygen consumption the ATP-con-
tent in acute heart failure is likewise within normal limits (Fig.
2). These results suggest that the reduction in the content of the
high energy phosphates CP and ATP in acute heart failure is
not the cause of insufficient myocardial function but rather an
adaptive mechanism to compensate for increased myocardial
oxygen consumption.
In vitro experiments have shown that in the heart the CP/Cr
system is directly related to mitochondrial function for several
reasons:
1. A specific mitochondrial isoform of creatine kinase
(CKmito) is expressed in the heart (18).
2. Cr stimulates mitochondrial respiration by lowering the
Michaelis constant (Km) of ADP with respect to mitochon-
drial control (66).
* Free energy of the ATP-system:
[ATP]
DGATP = DG0’ATP + R·T·ln
[ADP] · [Pi]
DG0’ATP = –30.5 [kJ/mol]
R = 8.31 [J/mol·K] (gas constant)
T = temperature [Kelvin]
[ADP], [Pi], [ATP] = concentrations of ADP, inorganic phosphate, and ATP
 A. M. Vogt and W. Kübler
Heart failure = energy deficit?
Fig. 1 The relation between myocardial creatine phosphate (CP) content
and myocardial oxygen consumption at normothermia. The variation of
CP content and of oxygen consumption was achieved in the following
ways (groups from left to right):
Group 1: Artificial cardiac arrest with cardioplegic solution II
Group 2: Artificial cardiac arrest with cardioplegic solution I
Group 3: Artificial cardiac arrest with KCI
Group 4: Empty beating heart; halothane anesthesia
Group 5: Empty beating heart; barbiturate anesthesia
Group 6: Working heart; halothane anesthesia
Group 7: Working heart; barbiturate anesthesia
Group “heart failure”: working heart; halothane anesthesia, and applica-
tion of angiotensin.
All experiments were performed in vivo by use of a heart-lung machine.
For experimental details see (37). A hyperbolic regression line and its
standard deviation (SR) are revealed (From (40)).
3. Cr stimulated mitochondrial respiratory rate is directly cor-
related with the activity of CKmito (20) probably due to a
functional coupling between CKmito and the ADP/ATP-
carrier of the inner mitochondrial membrane.
4. Stimulation of mitochondria by Cr increases the trans-
membrane [H+] gradient (20) which promotes ATP-syn-
thesis.
The importance of the CP/Cr system for respiratory control
and hence oxygen consumption in the whole heart can also be
demonstrated in vivo:
1. The degradation of CP during ischemia is directly related to
oxygen consumption before the ischemic period. For the
bulk of ATP no such relationship exists (Fig. 3 (40)).
3
2. There is an almost linear relationship between the Cr/CP
ratio and myocardial oxygen consumption. For the quotient
ADP/ATP no such relation can be demonstrated. Even after
correction for the free and unbound part of ADP, either by
using computer simulation data** or by calculating free
[ADP] from the adenylate kinase reaction, no relation
between [ADP] or the ADP/ATP ratio and myocardial oxy-
gen consumption can be observed (Fig. 4 (40)).
According to these results it can be suggested that the
Cr/CP ratio is linked to the regulation of myocardial oxygen
consumption. From the data presented it can furthermore be
calculated that by a more than 20-fold increase in myocardial
oxygen consumption from 0.5 to 12 ml·100 g–1·min–1 the free
energy of the CP/Cr system is reduced by more than 20 %. For
the same increase in myocardial oxygen consumption, how-
ever, the reduction in free energy of myocardial ATP/ADP
amounts only to less than 4 %. This comparatively small
decrease in the free energy of myocardial ATP/ADP is due to
a progressive displacement of the mass action ratio of the CK
reaction in favor of ATP synthesis with increasing myocardial
oxygen consumption (Fig. 5). In this way, in the heart a marked
stimulation of mitochondrial respiration can be achieved with-
out major impairment of free energy of the ATP/ADP system
preventing contractile failure with increasing workload and
hence energy demands (40).
** This computer simulation programm developed by Achs and Garfinkel
(1) is based on our experimental data (41).
4 Basic Research in Cardiology, Vol. 93, No. 1 (1998)
© Steinkopff Verlag 1998

Fig. 2 The relation between

myocardial adenosine triphos-
phate (ATP) content and myo-
cardial oxygen consumption at
normothermia. For experimental
conditions see Fig. 1. The linear
regression line and its standard
deviation (SR) are shown (From
(40)).

Fig. 3 Upper part: The relation between myocardial oxygen consump-
tion before ischemia and the velocity of creatine phosphate (∆CP/t) break-
down during ischemia. Variation of myocardial oxygen consumption and
of the velocity of CP breakdown was achieved by methods listed in Fig.
1. In addition the experiments were performed at different temperatures.
Lower part: The relation between myocardial oxygen consumption before
ischemia and the velocity of breakdown of the bulk of myocardial adeno-
sine triphosphate (∆ATP/t) during ischemia. The experimental conditions
were the same as in the upper part of Fig. 3 (From (40)).
Fig. 4 The relation between myocardial oxygen consumption and the
creatine/creatine phosphate (Cr/CP) ratio as well as the adenosine diphos-
phate/adenosine triphosphate (ADP/ATP) ratio of myocardial metabolite
content are shown. For Cr, CP, and ATP, total myocardial cell contents are
given: for ADP, only the free and unbound part (taken from calculations
of Achs and Garfinkel (1)) has been used for the calculations (From (40)).
 A. M. Vogt and W. Kübler
Heart failure = energy deficit?
Fig. 5 The mass action ratio of the creatine kinase (CK) reaction, cal-
culated from the cell contents of Cr, CP, ATP, and of the free and unbound
part of ADP (see Fig. 4). The data are given in relation to myocardial
oxygen consumption (From (40)).
This concept is in full agreement with the phosphocreatine
circuit model (10) in which the CP/Cr system fulfills several
functions: (a) because of the localization of CKmito with the
mitochondrial nucleotide translocase, CKmito can alter the local
ATP/ADP ratio (68). Due to high local ATP- and low ADP-
concentrations – as the result of oxidative phosphorylation –
the CKmito reaction facilitates the formation of ADP in this way
stimulating mitochondrial respiratory function. (b) The CP/Cr
system in addition is assumed to transport high energy bonds
from the site of production, the mitochondria, to the site of uti-
lization, the myofibrils (10). (c) At the myofibrillar site, the
local CK isoform (CKmyofib) catalyzes the resynthesis of ATP
from ADP (while CP is converted to Cr). Normal local ATP-
levels are achieved by 3 factors, which all favor the synthesis
of ATP from CP:
1. The standard free energy of hydrolysis of CP (–45 kJ/mol)
is greater than that of the terminal phosphate of ATP
(–30.5kJ/mol) (22, 65).
2. Acidosis shifts the CK reaction towards the formation of
ATP*** (44).
*** The apparent equilibrium constant (KCKapp) can be rewritten:
[CP] · [ADP] · [H+]
KCKapp =
[Cr] · [ATP]
5
3. With increasing myocardial oxygen consumption the appar-
ent equilibrium constant of the CK reaction is shifted
towards the formation of ATP as shown before (Fig. 5) (40).
Although factor 1 is valid only under standard “in vitro”
conditions, for thermodynamic reasons all 3 factors can be
expected to facilitate the transphosphorylation of ATP from
CP.
The CK system and the high energy phosphates
in chronic heart failure
Compared to acute heart failure, the alterations in the myocar-
dial CK system and in the HEP in chronic heart failure are
more pronounced.
In patients with dilated cardiomyopathy (DCM), Neubauer
et al. (50) demonstrated a marked reduction of the CP/ATP
ratio. In patients with severe heart failure (NYHA class
III–IV), the CP/ATP ratio was more depressed than in patients
with mild heart failure (NYHA class < III). A highly signifi-
cant linear relationship was found between the NYHA class
and the CP/ATP ratio (r = 0.60, p < 0.005). Recompensation
of these patients – mainly with diuretics and ACE inhibitors –
restored the depressed CP/ATP ratio.
In chronic heart failure of humans not only reduced
CP/ATP ratios were found. In addition, myocardial total Cr
levels are likewise reduced (by 40 to 57 %) (30, 45), whereas
no significant changes were found in the phosphodiester/ATP
ratios (50) and in the levels of adenine nucleotides including
ATP (controls: 36.9 ± 14.6 µmol/mg; DCM: 33.3 ± 9.4) (54).
Hence, in chronic heart failure of humans myocardial CP/Cr
ratios and ATP levels can be assumed to be within normal
limits.
Similar findings were obtained in animal experiments such
as the chronically infarcted rat heart (49). Like in humans the
myocardial CP- (–31 %, p < 0.05) and Cr levels (–35 %, p <
0.05) are reduced to approximately the same extent, so that the
CP/Cr ratio is virtually unchanged. Also the levels of ATP
(sham hearts: 28.3 ± 5.6 nmol/mg protein, infarcted hearts:
28.0 ± 3.0) and inorganic phosphate (P1, 11.3 ± 0.6 nmol/mg
protein vs. 12.6 ± 1.1) as well as the intracellular pH (7.13 ±
0.01 vs. 7.15 ± 0.01) are within normal limits. In addition, in
these hearts a significant reduction in total CK activity (6.5 ±
0.2 vs. 5.4 ± 0.3 IU/mg protein, p < 0.05) with a predominant
decrease in the mitochondrial isoform (from 35.2 ± 1.4 to 22.1
± 2.1 % of total CK) was observed.
The depressed CP levels and the reduced CK activity have
been interpreted as signs of an “energy deficit” (58). The
depressed CP levels in the presence of a normal CP/Cr ratio in
association with normal ATP contents, however, do not indi-
cate “energy starvation”. The alteration in myocardial CP- and
Cr-contents in heart failure are rather due to disturbances in the
myocardial uptake mechanisms for Cr (47, 68).
6 Basic Research in Cardiology, Vol. 93, No. 1 (1998)
© Steinkopff Verlag 1998
Likewise, the reduced myocardial CK activity in heart fail-
ure does not necessarily indicate that this reaction becomes
rate limiting for energy transfer in heart failure under normal
steady state conditions. In chronically infarcted rat hearts, ATP
synthesis via the CK reaction is reduced by approximately
50% (49). Despite this marked and pronounced decrease in
CK activity, CK reaction velocity to synthetize ATP still by far
exceeds ATP synthesis rates by aerobic and anaerobic gly-
colytic energy production (Table 1). According to these data
even in the failing heart ATP synthesis rates by aerobic or
anaerobic energy production are more than 6 times slower than
CK reaction velocity. Again, from these values an “energy
deficit” as cause or consequence of heart failure cannot be
derived.
Although it has been shown in rat hearts that the velocity of
the CK reaction changes in parallel with cardiac performance,
controversy still exists regarding the function of the CK reac-
tion under physiological conditions. To define the relation
between phosphoryl transfer via the CK reaction and the abil-
ity of the intact beating heart to do work, the group of Joanne
Ingwall inhibited CK directly by exposure to the sulfydryl
group reactant iodoacetamide (IA) (25). Under these condi-
tions in isolated perfused rat hearts, CK activity was markedly
depressed to less than 2 % of the control (from 6.6 ± 0.3 to 0.1
± 0.1 IU/mg protein). The CK isoenzyme profile was
unchanged suggesting non-selective IA inhibition of all isoen-
zymes. Myocardial ATP levels were normal (control: 25.0
µmol/g dry wt; IA: 23.0 ± 4.3) and CP levels reduced to 78 %
(control: 40.3 ± 7.3 µmol/g dry wt; IA: 31.8 ± 6.3). Neither
mitochondrial respiratory function nor actomyosin ATPase
were affected by IA.
After inhibition of CK with IA heart rate and left ventricu-
lar pressure were unchanged as might be expected under
steady state conditions in the presence of normal ATP- and
near normal CP-levels. Significant alterations in myocardial
function, however, were observed during stress conditions.
The increase in left ventricular developed pressure, induced
by increasing the perfusate’s calcium concentration, was
reduced from 64 to 39 mmHg and during norepinephrine per-
Table 1 ATP synthesis rates by the CK reaction and by aerobic ATP
production according to (49) recalculated using a more realistic P/O ratio
of 2.5. Values for anaerobic glycolytic energy production were taken from
(41). MI: chronic myocardial infarction; sham: sham operated control
animals.
ATP synthesis rates
sham MI
CK-reaction [mM/s] 10.8 ± 0.5 5.4 ± 0.5
= 100 % = 100 %
Aerobic (P/O-ratio 2.5) 7.3 % 14.7 %
Anaerobic glycolytic 6.5 % 13.1 %
fusion from 110 to 51 mmHg, respectively. According to these
results pharmacologic inhibition of the CK reaction reduces
myocardial contractile reserve by about 50 %. Recent experi-
ments with isolated perfused hearts from transgenic mice with
inherited CK isoenzyme knockouts revealed similar results (60).
Furthermore, in cardiomyopathic hamsters, a linear rela-
tionship was found between energy reserve via the CK reac-
tion and contracile reserve of the heart, induced with high Ca++
challenge (63). These concomitant decreases in the CK reac-
tion velocity and in the contractile reserve suggest that the
alterations in the CK system observed in chronic heart failure
are indicative of a reduced energy reserve.
According to these results, the alterations observed in the
CK system in chronic heart failure cannot be interpreted in
terms of an “energy deficit” (i.e., the excess of what is spent
over what is received on energy). “Energy reserve” (i.e.,
energy kept back for future use, to fill an emergency), however,
is markedly reduced in heart failure. Under steady state con-
ditions, a decreased “energy reserve” cannot be expected to
contribute to heart failure. However, under stress conditions
this mechanism becomes manifest by reducing contractile
reserve.
The mechanism by which this decreased “energy reserve”
induces depression of contractile reserve is an unsolved prob-
lem: inorganic phosphate, the degradation product of CP and
ATP, has been suggested as a substance inducing early dias-
tolic failure in the ischemic myocardium by trapping Ca++ and
mainly by desensitization of contractile proteins (39, 42).
However, according to published data (49), the myocardial Pi-
values in heart failure are within normal limits.
ATP depletion by insufficient resynthesis via the CK reac-
tion affecting the high affinity ATP binding sites with Km
values in the submicromolar range would induce rigor and
contracture (35, 39), but not heart failure. Furthermore, even
in severe heart failure the ATP levels are 3 orders of magnitude
above the critical level for high affinity ATP binding sites. For
these two reasons these high affinityATP binding sites are
extremely unlikely to affect heart failure.
There exists in addition low affinity regulatory binding sites
for ATP with Km values above the 100 micromolar range. By
reducing myocardial ATP levels ion pumps are allosterically
inhibited, such as the depolarizing Na+/Ca++ currents, the
opening of Ca++ channels and the Na+/Ca++ exchanger, the ATP
dependent K+ channels, and the Na+ and the Ca++ pump. These
ATP mediated allosteric effects on ion pumps could account
for reentrant ventricular tachyarrhythmias, decreased myocar-
dial contractility, and impaired relaxation (35). This hypothe-
sis, however, is based on the assumption that in heart failure
due to the reduced energy reserve via the CK system myocar-
dial ATP levels drop to such an extent that allosteric inhibitory
effects are induced. Until now this has neither been shown, nor
have reduced ATP levels or – as an indirect indicator –
depressed CP/Cr ratios been demonstrated.
 A. M. Vogt and W. Kübler
Heart failure = energy deficit?
Heart failure related to alterations in energy metabolism
Mitochondrial diseases
Mitochondrial diseases (reviewed in (4, 51)) involve many but
not all organ systems of the body. The different organ involve-
ment may be due to heteroplasmy or to variable proportions of
mutant and wild-type DNAs in various tissues. Furthermore,
the dependency on oxidative phosphorylation may be differ-
ent for different organs.
The Kearns Sayre syndrome (ophthalmoplegia and
retinopathy)
It is generally caused by large deletions of mitochondrial
DNA. The symptoms include: ptosis or ophthalmoplegia, pig-
mentary degeneration of the retina, short statue, cerebellar
signs, hearing loss, mental retardation, vestibular system dys-
function, and delayed puberty. The cardiac involvement con-
sists in disturbances in cardiac conduction, which may
progress to Adams-Stokes attacks or even sudden death.
The MERRF-syndrome (myoclonus epilepsy and ragged red
fibers)
This disease is caused by point mutations, e.g., adenine to
guanine (A-to-G) mutation at nucleotide position 8344 in the
mitochondrial DNA. Patients with this syndrome may suffer
from myoclonus, generalized convulsion, cerebellar ataxia,
muscular atrophy, abnormal EEG, elevated blood lactate and
pyruvate levels, and ragged red fibers. Cardiac involvement
may consists of cardiomegaly, which in rare cases may
progress to dilated cardiomyopathy, asymmetrical septal
hypertrophy, and diffuse hypokinesis of the left ventricle.
The MELA-syndrome (mitochondrial myopathy,
encephalopathy, lactic acidosis, and stroke-like episodes)
It is generally caused by point mutations, e.g., A-to-G muta-
tions at nucleotide 3243. The patients may show ragged red
fibers, short statue, seizures, and hemiparesis, hemianopia, or
cortical blindness. The cardiac involvement presents as sym-
metrical left ventricular hypertrophy with and without abnor-
mal wall motion.
The phenotype of mitochondrial diseases is predominantly
determined by neurological disorders and myopathies. There-
fore, the patients are rarely referred to a cardiologist, although
cardiac involvement may ultimately determine the patients’
prognosis. Several findings support the hypothesis that these
7
diseases are causally linked to a disturbed energy production
by oxidative phosphorylation:
Mitochondrial diseases can readily be detected using NMR
spectroscopy of skeletal muscle during mild exercise, where a
rapid fall of CP and a rise in Pi is observed (14, 32, 43). In
patients suffering from MELA syndrome with cardiac involve-
ment, endomyocardial bipsies revealed characteristic findings
similar to those seen in skeletal muscle biopsies from the same
patients where ragged red fibers and disturbances of the
enzymes involved in oxidative phosphorylation were demon-
strated (56). In cultured skin fibroblasts from a girl suffering
from a fatal systemic mitochondrial disease, activities of
enzymes of oxidative phosphorylation, pyruvate dehydroge-
nase, beta-oxidation, and other mitochondrial pathways were
markedly decreased (2).
The stunned and hibernating myocardium
It is generally accepted that the most frequent cause of heart
failure is coronary heart disease. Myocardial ischemia induces
an energy deficit, which may be transient with immediate
restoration of cardiac function as in an anginal attack or which
induces necrosis as in myocardial infarction. Under these con-
ditions, ischemia is the direct cause of the energy deficit, which
is thoroughly investigated both in patients and in animal
experiments.
There are, however, two distinct entities with ischemia-
induced dysfunction of reversibly damaged, viable myo-
cardium: the “stunned” and the “hibernating” myocardium.
They will briefly be discussed. In both conditions a steady state
of reversible myocardial dysfunction related to alterations in
cardiac energy metabolism was assumed, a hypothesis which
is not supported by newer findings.
The stunned myocardium
Despite restoration of adequate coronary blood flow, pro-
longed postischemic dysfunction persists depending on sever-
ity and duration of the preceding ischemic period (reviewed in
(11, 15, 36, 57)). This myocardium responds to positive
inotropic interventions, such as Ca++, digitalis, cate-
cholamines, and calcium sensitizers. The clinical implications
are rather simple: if signs and symptoms of heart failure are
present, positive inotropic drugs will be given. The underlying
mechanism has not been elucidated:
Since the ATP levels in the stunned myocardium are
depressed and recover slowly (17), the hypothesis was
advanced that this postischemic dysfunction may result from
an inability of the myocardium to resynthesize enough adenine
high-energy phosphates to sustain contractile function (55).
Reactive oxygen metabolites, generated in ischemic/reper-
8 Basic Research in Cardiology, Vol. 93, No. 1 (1998)
© Steinkopff Verlag 1998
fused myocardium (12), are regarded to impair mitochondrial
function and hence energy delivery (19, 67). There are, how-
ever, several findings that do not support this hypothesis:
1. No correlation exists between myocardial ATP levels and
recovery of contractility in several models of postischemic
dysfunction (23, 48).
2. The content in CP in the myocardium is normal or supra-
normal (“CP-overshoot”), implying that the phosphoryla-
tion potential of the mitochondria is not impaired (21, 24).
3. The stunned myocardium responds to inotropic stimuli with
a marked and sustained increase in contractility, even above
the baseline values. This striking inotropic response occurs
without an abnormal decrease in ATP- and CP-stores, indi-
cating that energy production is not impaired and can keep
pace even with high metabolic demands (3, 7).
4. Manipulations to increase ATP levels in the stunned
myocardium fail to increase myocardial function (28).
5. Although myocardial stunning is associated with a decrease
in myofibrillar CK activity and a reduction of free ADP (24),
the reversal of postischemic dysfunction by inotropic stim-
uli (7, 13, 31) implies that the residual activity of
CKmyofib is still sufficient to generate enough ATP even
under conditions of increased contractility.
The hibernating myocardium
It is characterized by an adaptive reduction of myocardial con-
tractile function in response to a reduction in myocardial blood
flow (53). In clinical conditions, immediate revascularization
to improve left ventricular function should be performed.
Parameters of myocardial energy metabolism – such as CP
content and lactate production – have been determined by
Schulz and Heusch (59). After 5 min of low-flow ischemia,
regional contractile function decreases, the CP content falls
from 7.91 ± 1.33 to 4.11 ± 2.00 µmol/g wet weight and lactate
consumption (2.67 ± 1.21 µmol/g/min) is reversed to net lac-
tate production (–1.12 ± 0.61) as a sign of anaerobic glycoly-
sis. With the extension of low-flow ischemia to 85 min, how-
ever, there is a tendency for recovery of CP content (5.78 ±
2.27) and attenuation of lactate production (–0.69 ± 0.44),
despite a further decrease in regional contractile function.
After infusion of dobutamine, regional contractile function
increases at the expense of a further decline in CP content
(3.44 ± 0.97) and increased lactate production (–2.75 ± 1.18).
The hypometabolic response of short-term hibernating
myocardium seems to be an actively downregulating process.
In the hibernating pig heart, the energy ratio (i.e., the ratio of
HEP production to HEP consumption in percent (27))
decreases from 0 % under baseline conditions to –17 % 10 min
after onset of regional low-flow ischemia, but subsequently
reverses to +12 % after 60 min (5). In a passively downregu-
lating process, the hypometabolic response could be expected
to only restore the balance between ATP consumption and
production, the finding of a positive energy ratio favors the
hypothesis of an actively downregulating process (52). In addi-
tion, the heart’s ability to downregulate ATP consumption
when ATP production is forcibly reduced following a limita-
tion in coronary blood flow is tightly linked. In pig hearts
undergoing a ramp reduction in LAD-flow to about 65 % over
30 min, a significant decrease in regional left ventricular sys-
tolic function develops (75 % reduction) without a sustained
fall in CP/ATP ratios and with no or minimal lactate produc-
tion (6). This again suggests an actively regulating feedback
mechanism to adapt contractile myocardial function to actual
ATP production.
At present, for the underlying mechanism and its trigger no
convincing hypothesis exists. Even if myocardial hibernation
is considered as a regulatory event to maintain myocardial
integrity and viability, it is conceivable that this adaptive mech-
anism is triggered by low flow ischemia.
Early diastolic failure in ischemia, decreased contractile
reserve in the presence of reduced energy reserve in chronic
heart failure, and reversible myocardial dysfunction in stunned
and hibernating myocardium may be due to identical or simi-
lar but still unknown mechanisms. In all these conditions the
alterations in myocardial energy metabolism do not satisfac-
torily explain the appearance of contractile dysfunction.
E

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