© 1995 American Heart Association, Inc.
Articles |
Antibody-Mediated Imbalance of Myocardial Energy Metabolism
A Causal Factor of Cardiac Failure?
From Medizinische Klinik B, Heinrich-Heine Universität, Düsseldorf, Germany.
Correspondence to Karsten Schulze, MD, Medizinische Klinik B, Heinrich-Heine Universität, Moorenstr 5, 40225 Düsseldorf, Germany.
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Abstract |
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Abstract The ADP-ATP carrier of the inner mitochondrial membrane is an autoantigen in myocarditis and dilated cardiomyopathy. Sera of patients with these diseases contain carrier-specific autoantibodies that inhibit the transmembrane nucleotide transport on isolated mitochondria. Guinea pigs immunized with the isolated ADP-ATP carrier protein also generate specific carrier-inactivating antibodies. In this study, we measured the cardiac function of guinea pigs immunized with the ADP-ATP carrier by determining the external heart work (EHW) of their isolated perfused spontaneously beating hearts stimulated by 4.0 mmol/L calcium and aortic ligature. Further, the electrogenic transport activity of the ADP-ATP carrier was estimated by calculating the cytosolic-mitochondrial difference of the phosphorylation potential of ATP [
G(cyt-mit)] in the
freeze-clamped isolated hearts by nonaqueous fractionation. The EHW of
immunized guinea pigs was seen to be reduced by 54%
(P<.005) compared with nonimmunized control guinea pigs,
and G(cyt-mit) declined from 4.9 kJ/mol ATP in nonimmunized
control hearts to 2.3 kJ/mol ATP in the hearts of the immunized guinea
pigs (P<.005). The decisive result of this study, however,
is the close relation observed between the magnitude of reduction of
G(cyt-mit) and the size of the decrease in EHW (r=.87).
Therefore, it seems plausible that antibody-mediated carrier
dysfunction (creating the observed imbalance in myocardial energy
metabolism) is responsible for the impairment of cardiac function. Our
data support the hypothesis that immunopathic mechanisms in myocarditis
and dilated cardiomyopathy can trigger subsequent heart failure. The
underlying pathophysiological reason seems to be a metabolic disorder
initiated by the antibody-mediated inactivation of the ADP-ATP carrier.
Key Words: • ADP-ATP carrier • phosphorylation potential • myocarditis • cardiomyopathy
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Both clinical and experimental data support immunopathic mechanisms as playing a major role in the pathogenesis of myocarditis and dilated cardiomyopathy.1 2 3 4 5 6 7 8 Most clinical cases of myocarditis in humans are suspected to be of viral etiology. However, the mechanisms by which an acute viral infection or chronic virus persistence alter the immune system have not yet been completely disclosed. Autoantibodies directed against a wide spectrum of myocardial antigens are found in myocarditis,5 6 7 8 9 10 11 12 13 14 15 but it remains doubtful whether all these antibodies are of relevance for the development of subsequent heart failure.
In previous studies, we have been able to identify exclusively the ADP-ATP carrier, the nucleotide transporting protein of the inner mitochondrial membrane, as an autoantigen in patients with myocarditis and dilated cardiomyopathy.15 No antibodies against the ADP-ATP carrier were found in the sera of patients suffering from the ischemic, hypertrophic, or alcohol-toxic forms of cardiomyopathy.15 16 17 The autoantibodies were characterized as organ and conformation specific and inhibit nucleotide exchange in vitro by blocking the substrate binding site of the carrier protein.17 18
In the intact isolated beating animal heart, the antibodies against the
ADP-ATP carrier were able to affect the carrier function as well. When
guinea pigs were immunized with the isolated purified carrier protein,
myocardial energy metabolism was disturbed in such a manner that the
cytosolic-mitochondrial difference of the phosphorylation potential
[G(cyt-mit)] was lowered.19 This important parameter
of the energy state of the myocyte is regulated by the ADP-ATP carrier
and reflects its function.20 21 Driven by the membrane
potential,22 the active carrier generates a transmembrane
phosphorylation potential difference that is 
4.5 kJ/mol ATP higher
in the cytosol.19 In the hearts of animals immunized with
the ADP-ATP carrier, this transmembrane potential difference was found
to be considerably lower, although cardiac work was kept constant,
which indicates a work-independent reduction in transmembrane
nucleotide transport activity.19
These findings argue against the notion that the antibodies found in myocarditis and dilated cardiomyopathy are a mere epiphenomenon. When the hearts were stimulated to their individual maximum, we could further show that heart function was depressed in animals immunized with the ADP-ATP carrier,23 but we did not prove that the antibody-mediated disturbances in energy metabolism led to the cardiac dysfunction.
However, this proof is essential in order to define an autoimmunologically triggered pathophysiological mechanism of substantial relevance in myocarditis and dilated cardiomyopathy. Therfore, it was the aim of the present study to assess whether a link exists between the degree of impairment in energy metabolism and the magnitude of cardiac dysfunction.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Immunization Procedure
Twenty-five of 36 female guinea pigs matching in strain (Pirbright White, Ivanovas, Munich, Germany), age, and weight (1000 g) were immunized with the ADP-ATP carrier isolated from bovine heart mitochondria. The isolation of mitochondria and the solubilization and isolation of the ADP-ATP carrier followed the procedures previously described.17 For immunization, 50 µg of carrier protein was injected (30 µg SC and 20 µg IP) every other week for a period of 4 months. The protein (0.1 mg protein suspended in 100 mmol/L NaCl, 10 mmol/L MOPS, and 0.5% Triton X-100) was emulsified with an equal volume of Freund's adjuvant for subcutaneous injections. For the first injection, Freund's complete adjuvant was used; all subsequent booster injections were administered with Freund's incomplete adjuvant. The antigen injected intraperitoneally was always given without Freund's adjuvant. The 11 remaining guinea pigs, forming the control collective, were subjected to the same immunization protocol omitting the antigen. This protocol conformed to the guidelines of the American Physiological Society.
Indirect Micro–Solid-Phase Radioimmunoassay
For detection of antibodies against the ADP-ATP carrier in a
solid-phase radioimmunoassay, 5 mL of blood was taken from the guinea
pigs before immunization (preimmune sera), after the second booster
injection, and when the animals were killed. The assay was performed on
96-well polyvinyl microtiter plates (Dynatech Scientific Inc). The
plates were coated with 100 µL ADP-ATP carrier protein per well
diluted to 0.5 mg/mL in 100 mmol/L NaCl, 10 mmol/L MOPS, and 0.5%
Triton X-100 (pH 7.2) and incubated at 4°C for 4 hours. After the
wells were washed three times with 3% fetal calf serum in
phosphate-buffered saline, the precoated plates were incubated with 100
µL of 3% fetal calf serum for 1 hour at 4°C to block any remaining
active binding sites of the polyvinyl plates. After a further washing,
the antigen-coated wells were incubated overnight at 4°C with 90 µL
of the serum to be tested. Subsequent to the washing, specifically
bound antibodies were detected with iodinated protein A (100 000 cpm
per well, New England Nuclear). This involved incubation for 4 hours at
4°C in which the wells were washed three times, allowed to dry, and
counted in a gamma spectrometer. All assays were performed in
duplicate. The separate controls for nonspecific binding, performed
parallel to each test with no antigen, no serum, and control serum,
routinely yielded values 2% to 6% of the total activity.
Western Blot
The isolated ADP-ATP carrier, total protein from guinea
pig heart mitochondria, and marker proteins were separated on sodium
dodecyl sulfate–polyacrylamide slab gels. One section of the gel was
stained with Coomassie blue, and the other section was
electrophoretically blotted onto nitrocellulose (0.45 mm, Bio-Rad),
which was sandwiched between filter paper and Scotchbrite pads that
were supported on a porous plastic grid. The running buffer (pH 8.3)
contained 25 mmol/L Tris, 200 mmol/L glycine, and 30% methanol. The
electrophoretic transfer was run overnight at 4°C with 0.2 A. The
nitrocellulose was then incubated for 2 hours in 50 mmol/L Tris/HCl (pH
7.4) and 150 mmol/L NaCl (TBS) supplemented with 2.5% bovine serum
albumin (BSA). To remove unbound antibodies, six washings of 5 minutes
each were performed in TBS without BSA. Those antibodies that remained
bound to the nitrocellulose were stained by horseradish
peroxidase–conjugated anti-IgG.
In Vitro Measurement of the Adenine Nucleotide Transport
The ability of the individually generated antibodies to inhibit
the nucleotide transport was tested in vitro by measuring the exchange
of 14C-labeled ADP of isolated mitochondria. Aliquots (20
mg) of guinea pig mitochondria were loaded with 0.8 µCi
[14C]ADP each. The ADP exchange was started by adding 10
µL unlabeled ADP (10 mmol/L) to 200 µL of suspended mitochondria.
After 40 seconds, the ADP transport was stopped by adding
carboxyatractyloside to the suspension. The value for background
radioactivity (control) was obtained by adding carboxyatractyloside
only (no ADP). The adenine nucleotide translocation, being a 1:1
exchange between intramitochondrial and extramitochondrial nucleotides,
was calculated as percent exchange of the total intramitochondrial
content (total) according to the following equation:
 | (1) |
The Working Heart Preparation
According to the Langendorff technique, the isolated guinea pig
hearts were first retrogradely perfused via an aortic cannula. The
nonrecirculating perfusion medium was a modified Krebs-Henseleit buffer
containing (mmol/L) NaCl 127, KCl 4.7, NaHCO3 24.9,
CaCl2 1.25, MgSO4 0.6, and
KH2PO4 1.2, which was enriched with 0.3 mmol/L
pyruvate, 5.5 mmol/L glucose, and 5 U/L insulin. The buffer was
equilibrated at 37°C with 94.4% O2 and 5.6%
CO2 (pH 7.4). After 15 minutes of stabilization, the
perfusate was applied via a cannula tied into the left atrium. All
other atrial openings were ligated. The preload and afterload were set
to 12 and 80 cm H2O, respectively. The right atrial veins
were ligated, and the coronary venous effluent was drained through a
cannula inserted in the pulmonary artery. No external work was
performed by the right ventricle.
Atrial filling and aortic pressures were monitored by Statham
P23BB and P23Db strain gauges (Gould), respectively. Heart rate was
derived from the phasic pressure signal with a Beckman
cardiotachometer. All parameters were recorded on a Beckman Dynograph
R411. External heart work was calculated as the sum of (cardiac
outputxpressure gradient across the left
ventricle)+acceleration work [
xejected
volumex(mean velocity of flow)2] during ejection.
The myocardial oxygen consumption (M
O2)
was derived from the difference of O2 tension between
aortic perfusate and coronary effluent, which was measured with two
Clark-type electrodes (Bachofer), and the coronary flow rate. The
lactate release into the coronary effluent was measured
enzymatically.24
To enhance metabolic demand, all hearts (control and immunized groups) were stimulated by applying calcium at a high concentration (perfusate concentration, 4.0 mmol/L). In addition, after a further stabilization of 30 minutes, the aorta was ligated to induce a maximal pressure load. Hemodynamic parameters were measured against the occluded aorta after 40 minutes of work.
Nonaqueous Fractionation
To avoid further metabolic processes, the freeze-clamped hearts
were pulverized in a mortar filled with liquid nitrogen, lyophilized,
and stored in heptane/carbon tetrachloride. During lyophilization, all
formerly dissolved substances (eg, metabolites and enzymes) cling to
the membrane wall of their respective cellular compartment. After
ultrasonic disruption of the cells into small membrane fragments,
insufficiently homogenized particles, mainly consisting of connective
tissue, were removed by successive filtration through columns filled
with glass beads of 1.0- and 0.4-mm diameter. The purified homogenate
was then subjected to density-gradient centrifugation (4 hours at
16 000g). The density gradients (1.29 to 1.38 g/mL) were
produced by a continuous variation of the volume ratio of the two
constituents heptane (0.69 g/mL) and carbon tetrachloride (1.59 g/mL).
Since lyophilized mitochondrial membranes are lighter than cytosolic
structures, fractions with differing proportions of cytosolic and
mitochondrial proteins can be obtained.25 Each of the
eight fractions per gradient was subdivided into two aliquots. In the
first aliquot, the total protein content and the activities of the
cytosolic and mitochondrial marker enzymes, phosphoglycerate kinase
(PGK) and citrate synthase (CS), respectively, were determined. In the
second aliquot, the contents of phosphate, ADP, ATP, creatine, and
creatine phosphate were analyzed. Protein was measured according to the
method of Lowry et al,26 phosphate was measured
colorimetrically,27 and all other tests were enzymatic
analyses.28
Calculation of Intracellular Metabolite Contents
The known total metabolite content (M) in each fraction of the
density gradient is the sum of its mitochondrial (mit) and cytosolic
(cyt) portions:
 | (2) |
 | (3) |
 | (4) |
results in the
following linear expression:
 | (5) |
and 4. To derive
concentrations, these contents were first referred to the protein
contents of the corresponding compartment. Then, subcellular
concentrations were obtained assuming 3.8 µL water per milligram
cytosolic protein and 1.8 µL water per milligram protein in the
mitochondria.29 30 Since most of the cytosolic ADP is
bound to the contractile system of the heart muscle, the free cytosolic
ADP was calculated from the creatine phosphokinase (CPK) reaction,
assuming an intracellular hydrogen concentration of pH 7.05 and an
equilibrium constant of
KCPK=2.04 · 10-9 31 32 :
 | (6) |
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G of ATP (GATP), given
as
 | (7) |
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Statistical Analyses
The two-tailed Student's t tests for unpaired and
for combined samples were used. Values are presented as mean±SD.
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Results |
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During the immunization period, two guinea pigs of the immunized group died. In the sera of all immunized animals, an increase of antibodies against the ADP-ATP carrier was detected in the solid-phase radioimmunoassay after 4 months of immunization. The data are shown in Table 1
. The generation of specific antibodies was
further confirmed by Western blot, whereby the nitrocellulose blots
incubated successively with the serum of immunized guinea pigs and then
with horseradish peroxidase–conjugated anti-IgG had a positive
staining of the ADP-ATP carrier protein in all cases. All preimmune
sera, however, were nonreactive for the ADP-ATP carrier in
radioimmunoassay and Western blot. A representative blot is shown
in Fig 1.
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Table 1 also shows the amount of inhibition of ADP exchange in isolated
mitochondria. As observed in all previous experiments, no apparent
correlation exists between antibody generation and in vitro inhibition
of the nucleotide transport. In 13 of the 23 sera of immunized animals
tested, the in vitro ADP exchange inhibition exceeded the mean±2 SD
level of the control sera. These animals were regarded as possessing
carrier-inactivating antibodies and were defined as the in
vitro–positive subgroup. Fig 2 shows the linear
regression plot between the in vitro ADP exchange inhibition and
G(cyt-mit). This plot demonstrates the close relation of the two
parameters that indicate in vitro antibody-mediated carrier inhibition
and the in vivo effect of carrier inhibition on myocardial energy
metabolism.
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indicates nonimmunized control
guinea pigs (n=9); 
, immunized and in vitro–positive (serological
nucleotide transport inhibition) guinea pigs (n=11).All hearts of the control group (n=11) and of the immunized group showing a positive in vitro inhibition of the nucleotide transport (n=13) were isolated as working heart preparations and metabolically stimulated by high calcium concentration in the perfusate (4.0 mmol/L) and 40 minutes of aortic ligature. Afterward, hemodynamic data were recorded, and the oxygen tension and lactate concentration in the coronary effluent were measured. Finally, these hearts, except for two control hearts and two hearts from the immunized group, were freeze-clamped for the measurement of cytosolic and mitochondrial high-energy phosphate contents as described above.
The hemodynamic data comprising heart rate, mean aortic pressure,
coronary flow, stroke volume, and external heart work are shown in
Table 2 and in Fig 3. Heart rate did not
differ significantly, whereas mean arterial pressure (-30%,
P<.001), coronary flow (-37%, P<.005), stroke
volume (-30%, P<.005), and external heart work (-54%,
P<.001) were significantly suppressed in the hearts from
immunized animals when compared with the respective values from the
control hearts of nonimmunized animals. The myocardial oxygen
extraction, MO2, and the lactate release
into the coronary effluent are listed in Table 3 and
displayed in Fig 4. Myocardial oxygen extraction did not
differ significantly between control and immunized groups.
MO2 was lowered in the immunized hearts
by 39% (P<.001) compared with the control group. Lactate
release into the coronary effluent was increased by 110% in the
immunized group (P<.01). As a second measure of
MO2, the rate-pressure product (heart
ratexmean arterial pressure) was calculated (Table 2). It was found to
correlate closely to the external heart work (r=.90) and
showed a decrease of 33% (P<.001) in the immunized group
compared with the control group. The rate-pressure product and external
heart work correlate with the directly measured
MO2 (r=.71 and .81,
respectively), with external heart work showing the better relation to
MO2 than the rate-pressure product.
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The metabolic data of the control and of the immunized groups are
demonstrated in Table 4. Neither cytosolic nor
mitochondrial phosphate concentrations differed between control and
immunized hearts. Cytosolic ADP, ATP, and creatine were also shown not
to be altered significantly. Cytosolic creatine phosphate, however, was
found to be reduced from 28.5±5.9 mmol/L in the control group to
23.6±3.7 mmol/L in the immunized group (P<.05).
Mitochondrial ATP markedly increased from 8.2±1.2 mmol/L in the
control group to 12.4±3.2 mmol/L in the immunized group
(P<.005), whereas mitochondrial ADP decreased from 2.4±0.4
mmol/L in the control group to 1.6±0.5 mmol/L in the immunized group
(P<.001). The calculated combined parameters were altered
significantly both cytosolically and mitochondrially (see Table 5 and
Fig 5). The ATP to ADP ratio declined in
the cytosol from 59±14 to 47±8 (P<.05) and rose in the
mitochondria from 3.5±0.7 to 9.3±5.4 (P<.005). Cytosolic
G was lowered from 19.6±0.7 to 18.9±0.6 kJ/mol ATP
(P<.05), whereby mitochondrial G increased from
14.7±0.4 to 16.6±1.3 kJ/mol ATP (P<.005). Through a
combination of both G values, G(cyt-mit), which reflects the
electrogenic nucleotide transport activity of the ADP-ATP carrier, was
found to be reduced by >50%, falling from the control value of
4.9±0.6 to 2.3±1.1 kJ/mol ATP in the hearts of the immunized animals.
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Finally, Fig 6 demonstrates the relation between the
impairment of energy metabolism, represented by G(cyt-mit) and
the myocardial function, represented by the external heart work.
The regression plot shows that the maximum work the guinea pig hearts
perform after being immunized with the ADP-ATP carrier protein
correlates with the magnitude of G(cyt-mit) reduction
(r=.87).
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Discussion |
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All guinea pigs immunized with the isolated purified ADP-ATP carrier generated carrier-specific antibodies, as confirmed by radioimmunoassay. The specificity of these antibodies was further demonstrated by Western blot and by the measurement of the nucleotide transport rate on isolated mitochondria. When all these experiments were carried through by using either mitochondria or the carrier protein from liver and kidney, no binding or functional activity of the antibodies was evident, thus showing a high organ specificity of the anti–heart carrier antibodies.15 17 Immunohistochemical studies by direct immunofluorescence and peroxidase-antiperoxidase staining of cryosections of the myocardium from immunized animals revealed an immunoglobulin binding to the cell surface and to intracellular structures.19
Immunization with the isolated ADP-ATP carrier results in a rise of
polyclonal antibodies directed against various antigenic determinants
of the protein. Depending on their binding site, not all antibody
subpopulations need be active in influencing the carrier function.
Therefore, the antibody "amount" as tested in the
radioimmunoassay does not necessarily correlate with their
carrier-inactivating potency. However, 13 of the total of 23 assessed
sera from immunized animals showed a lowered rate of the nucleotide
transport in isolated mitochondria. Although the results from this in
vitro system and from the isolated perfused intact beating heart are
not directly comparable, the magnitude of carrier inhibition in vitro
correlates with the deterioration of energy metabolism "in vivo,"
as measured by G(cyt-mit). This shows the possible direct affection
of the carrier by the antibodies, although indirect mechanisms of
action are imaginable as well.
The results of antibody-mediated deterioration of cardiac energy
metabolism confirmed our findings in previous studies.19
We find a marked increase in the mitochondrial ATP concentration and a
decrease in mitochondrial ADP, resulting in a 166% rise
(P<.005) of the ATP/ADP quotient in this compartment
compared with the nonimmunized control group. As a consequence, the
calculated concentration term of the mitochondrial phosphorylation
potential of ATP (G) increased from 14.7 (control group) to 16.6
(immunized group) kJ/mol ATP (P<.005). The cytosolic
concentrations of the high-energy phosphates were changed in opposition
but to a lesser extent. Nevertheless, the cytosolic ATP-to-ADP ratio
and G decreased significantly (P<.05). More than the
cytosolic ATP (no significant loss), the creatine phosphate
concentration decreased from 28.5 (control group) to 23.6 (immunized
group) mmol/L (P<.05). This different susceptibility of
cytosolic ATP and creatine phosphate to the assumed lowered activity of
the ADP-ATP carrier can be explained by two lines of reasoning. First,
the mitochondrial CPK is located in the direct neighborhood of the
ADP-ATP carrier at the inner mitochondrial membrane.33
This carrier/phosphokinase complex probably transforms most of the
outward shifted ATP very effectively into creatine phosphate.
Therefore, any impairment of the carrier function should predominantly
affect the cytosolic creatine phosphate concentration before affecting
the cytosolic ATP concentration. Second, a higher lactate concentration
in the coronary effluent from the hearts of immunized animals (3.0
versus 1.4 mmol/g per minute in control hearts, P<.005)
argues in favor of an enhanced rate of anaerobic glycolysis to
compensate for the infringed delivery of aerobically supplied
high-energy phosphates. Although even maximally stimulated glycolysis
might not be sufficient to totally substitute the cytosolic ATP
demands,34 it should at least damp any cytosolic ATP
reduction.
As a consequence of the reported mitochondrial and cytosolic changes in
myocardial high-energy phosphate metabolism after immunizing guinea
pigs with the ADP-ATP carrier, G(cyt-mit) was found to be strongly
affected. We measured a >50% reduction of this parameter (from 4.9
kJ/mol ATP in nonimmunized control hearts to 2.3 kJ/mol ATP in the
hearts of the immunized animals, which had generated
carrier-inactivating antibodies). This "collapse" of
G(cyt-mit) should be the result of a deterioration of the function
of the ADP-ATP carrier, because its activity provides this
transmembrane potential difference.20 Our reported value
for G(cyt-mit) correlates well with earlier results and with data
from other laboratories.19 25 35 It is not likely that any
reduced activity of oxidative phosphorylation such as hypoxia or
limited substrate supply had lowered the mitochondrial membrane
potential, the "driving force" for the electrogenic carrier
activity. Had this occurred, mitochondrial ATP would be expected to be
diminished because of its reduced synthesis. Our observed very high
mitochondrial ATP concentration in the hearts of the immunized animals
argues against any scenario of reduced oxidative phosphorylation.
Hypoxia, in particular, could be excluded because the oxygen
concentration in the coronary-venous effluent from the hearts of
immunized animals did not differ from the value in the control hearts
(see Fig 3). In addition, coronary autoregulation was intact, and the
lactate release of all the control hearts was very low.
The hemodynamic recordings showed major differences between the isolated hearts of nonimmunized control guinea pigs and those of guinea pigs immunized with the ADP-ATP carrier. The mean developed aortic pressure was found to be increased by 30%; coronary flow, by 37%; and the stroke volume, by 30% (P<.005 for all parameters). The calculated external heart work was lowered by 54% (P<.005).
The major result of this experimental study, however, is shown in Fig 6, where the external heart work is plotted against G(cyt-mit). The
correlation coefficient (r=.87) indicates a close linearity
between those decisive parameters of cardiac cellular energy metabolism
and cardiac function. It seems obvious from these data that the more
the function of the ADP-ATP carrier was reduced, the more the energy
metabolism was infringed and the more pronounced cardiac function
failed. However, it may be argued that the fact that metabolism and
function are correlated with one another does not indicate that the
metabolic abnormality caused the functional one. One could also object
that different work loads of the heart themselves influence energy
metabolism. A work-dependent reduction of G(cyt-mit) could in fact
be demonstrated.25 However, in a previous study we were
able to show that under the influence of specific anti–ADP-ATP carrier
antibodies, similar changes in energy metabolism occurred even if all
hearts were submaximally and identically stimulated and thus were
uniformly performing exactly the same work.19 Therefore,
the reverse relation, that of cardiac function determining cardiac
energy metabolism, cannot be the sole explanation of our data. A second
reason that a primarily antibody-induced reduction of cardiac function
with a secondary change in energy metabolism seems doubtful is that the
in vitro inhibition of the nucleotide transport on isolated
mitochondria correlates much better with the phosphorylation potential
difference than with any hemodynamic parameter. Although correlation
does not necessarily indicate causation, it seems obvious that the
antibody-triggered disorder first alters the energy metabolism and then
leads to the infringed cardiac function.
In conclusion, the present data show that organ function can be influenced by an immunologically triggered metabolic disorder. The correlation of metabolic changes with heart function was demonstrated. This metabolic impairment occurs by antibody-induced affliction of an intracellular functional protein, the mitochondrial ADP-ATP carrier. The hereby caused antibody-mediated cardiac failure uncovers an immunologic mechanism, hitherto unknown. Our data argue in favor of the hypothesis that the antibodies against the ADP-ATP carrier found in the sera of patients with myocarditis and dilated cardiomyopathy16 17 are not merely an epiphenomenon of these diseases but might play an important pathophysiological role.
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Acknowledgments |
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This study was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 189-B8).
Received August 9, 1994; accepted September 12, 1994.
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