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Departments of Medicine and Radiology and Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, Minnesota 55455
Submitted 23 December 2002 ; accepted in final form 4 April 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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)
in all groups and decreased PCr/ATP in the normal and LVH groups. During
continuing catecholamine infusion, DNP (2–8 mg/kg iv) caused further
increases of
in normal and LVH hearts with no change in PCr/ATP. In contrast, DNP caused no
increase in
in the failing hearts; the associated decrease of PCr/ATP suggests that DNP
decreased the mitochondrial proton gradient, thereby causing ADP to increase
to maintain adequate ATP synthesis.
heart failure; left ventricular hypertrophy; mitochondria; high-energy phosphates; nuclear magnetic resonance
-adrenergic receptors and the downstream
adenylyl cyclase system (25)
make it even more difficult to determine whether ATP synthetic capacity limits
contractile performance. Hence, the hypothesis that primary "energy
starvation" limits function in heart failure
(14) remains to be rigorously
tested in vivo despite evidence that left ventricular (LV) hypertrophy (LVH)
and congestive heart failure (CHF) are associated with abnormalities of
myocardial energy metabolism
(2,
21,
22,
38,
39).
Consequently, the present study was performed to determine whether
administration of a classical mitochondrial uncoupling agent
[2,4-dinitrophenol (DNP)] could further increase myocardial oxygen consumption
()
in hearts with compensated LVH or overt cardiac failure that were already
functioning at a high work state produced by catecholamine stimulation. DNP
accelerates intramitochondrial metabolism proximal to ATP synthase by
decreasing the proton gradient across the inner mitochondrial membrane
(17,
30). In response to DNP,
increases in concert with intermediary metabolism and electron transport
activity to maintain the mitochondrial proton gradient that drives ATP
synthesis (15,
17,
30). Although it is unlikely
that DNP can define the maximal oxygen utilization capacity in the intact
heart (8), it can be used to
determine whether there is a reserve capacity of the reaction sequences that
generate the mitochondrial proton gradient required to support ATP synthase
activity. We hypothesized that if the capacities of the energetic reactions
proximal to ATP synthase constrained mechanical performance during high work
states, then DNP would not cause a further increase of
and might cause deterioration of mechanical performance and myocardial
high-energy phosphate (HEP) content. Measurements of myocardial HEP levels
were made with 31P NMR spectroscopy. Because of concerns that
abnormalities of perfusion or diffusion might limit oxygen delivery and
thereby impair respiratory rates in the hypertrophied or failing hearts,
myocyte oxygenation was assessed using 1H NMR spectroscopy.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Production of LVH. Sixteen Yorkshire pigs at 
45 days of age
were anesthetized with pentobarbital sodium (25–30 mg/kg iv), intubated,
and ventilated with a respirator. A right thoracotomy was performed in the
third intercostal space, and the ascending aorta, 1.5 cm above the aortic
valve, was mobilized and encircled with a polyethylene band 2.5 mm in width.
While LV and distal aortic pressures were simultaneously measured, the band
was tightened until a 70-mmHg peak systolic pressure gradient was achieved
across the narrowing. The chest was then closed, the pneumothorax was
evacuated, and the animals were allowed to recover. LVH occurred progressively
as the area of aortic constriction remained fixed in the face of normal body
growth. Two months after being banded, animals were returned to the laboratory
for study.
Experimental preparation. Ten normal pigs and twenty-one pigs with
LVH were premedicated with morphine sulfate (l mg/kg sc) and anesthetized with
pentobarbital (30 mg/kg iv, followed by an infusion of 4 mg ·
kg–1 · h–1). A
smaller dose of pentobarbital (20 mg/kg iv) was used for animals with CHF
to prevent loss of animals from general anesthesia. Animals were intubated and
ventilated with a respirator with supplemental oxygen; arterial blood gases
and pH were maintained within the physiological range. A polyvinyl chloride
catheter (3.0 mm outer diameter) filled with heparin-saline was introduced
into the right femoral artery and advanced into the ascending aorta. A left
thoracotomy was performed in the fifth intercostal space, and the heart was
suspended in a pericardial cradle. A heparin-saline-filled catheter was
introduced into the LV through the apical dimple and secured with a
purse-string suture. A similar catheter was placed into the left atrium
through the atrial appendage. A catheter was also introduced into the anterior
coronary vein via the right atrial appendage. An NMR surface coil was sutured
to the anterior LV wall overlying the region perfused by the left anterior
descending coronary artery. The surface coil was constructed of a single turn
of copper wire and incorporated a 33-pF capacitor; surface coils were 28 mm in
diameter. The surface coil leads were connected to a balanced-tuned circuit
external and perpendicular to the thoracotomy incision. The pericardial cradle
was released, and the heart was allowed to assume its normal position. The
animals were then placed in a Lucite cradle and positioned within the magnet.
Arterial blood gases were measured every 15 min, and the respirator was
adjusted to maintain the PO2,
PCO2, and pH in the physiological range.
Myocardial blood flow. Myocardial blood flow was measured with microspheres (15 µm in diameter) labeled with 141Ce, 51Cr, 95Nb, 85Sr, or 46Sc (NEN; Boston, MA) as previously described (3). Blood flow was expressed as milliliters per minute per gram of myocardium.
31P NMR spectroscopic technique. Our NMR spectroscopic
methods have been described in detail previously
(3,
10,
11,
29). Measurements were
performed in a 40-cm bore 4.7-T magnet interfaced with a SISCO (Spectroscopy
Imaging Systems; Fremont, CA) computer console. The LV pressure signal was
used to gate NMR data acquisition to the cardiac cycle, whereas respiratory
gating was achieved by triggering the ventilator to the cardiac cycle between
data acquisitions. 31P and 1H NMR frequencies were 81
and 200.1 MHz, respectively. Spectra were recorded in late diastole with a
pulse repetition time of 6–7 s. This repetition time allowed full
relaxation for ATP and Pi resonances and 90% relaxation of the
phosphocreatine (PCr) resonance; PCr resonance intensities were corrected for
this minor saturation. Radiofrequency transmission and signal detection were
performed with a 28-mm-diameter surface coil dually tuned for both
1H and 31P measurements. A capillary containing 15 µl
of 3 M phosphonoacetic acid was placed at the coil center to serve as a
reference. The proton signal from water was used to homogenize the magnetic
field and adjust the position of the animal in the magnet so that the coil was
at or near the magnet and gradient isocenters. Spectra were obtained with the
image-selected in vivo spectroscopy (ISIS) method, which defined a column 1.8
x 1.8 cm2 perpendicular to the LV wall. 31P signal
excitation was achieved with a 90°, adiabatic, B1-insensitive,
BIR-4 pulse. All chemical shifts were measured relative to the PCr peak, which
was assigned a chemical shift of –2.55 ppm relative to 85%
phosphonoacetic acid at 0 ppm.
Resonance intensities were quantified using integration routines provided
by SISCO software. The ATP
resonance was used for ATP determination.
Because data were acquired with the transmitter frequency positioned between
the ATP and PCr resonances, off resonance effects on these peaks were
virtually nonexistent. Numerical values for PCr and ATP were expressed as
ratios of PCr to ATP (PCr/ATP). Pi levels were measured as changes
from baseline values (
Pi) using integrals obtained in the region
covering the Pi resonance and are presented as
Pi/PCr. ADP levels in each group were calculated using
chemically measured total creatine and ATP levels, and 31P NMR
determined PCr and intracellular pH levels as previously described
(16).
1H NMR spectroscopic technique. Determination of
deoxymyoglobin (Mb-
) using the 1H NMR method has previously
been reported in detail (5,
38). In brief, radiofrequency
transmission and signal detection were performed with the dually tuned
28-mm-diameter surface coil. A single-pulse collection sequence with a
frequency-selective gauss excitation pulse (1 ms) was used to selectively
excite the N- proton signal of the proximal histidine in Mb-. A
short repetition time (25 ms) was used due to the short T1 of
Mb-. Each spectrum is acquired in 5 min (10,000 free induction decays).
Although the short T1 of Mb- and fast acquisition prevent
gating to the cardiac cycle, the signal loss due to motion was negligible due
to the inherently broad line width of the Mb- peak.
Hemodynamic measurements. Aortic and LV pressures were monitored with pressure transducers positioned at the midchest level. Data were recorded on an eight-channel direct writing recorder (Coulbourne Instrument; Lehigh Valley, PA). LV pressure was recorded at normal and high gain for measurement of end-diastolic pressure.
Experimental protocol. Hemodynamic measurements and NMR spectra
were first obtained under basal conditions. Midway through the 10-min NMR
data-acquisition period, a microsphere injection was performed for
determination of myocardial blood flow. After baseline data were obtained,
dobutamine and dopamine were infused simultaneously (each 20 µg ·
kg–1 · min–1
iv) to induce a high cardiac work state. After 10 min was allowed to
achieve a steady state, all measurements were repeated. After completion of
data acquisition, while the dobutamine and dopamine infusion continued, four
sequential 5-min infusions of DNP (each 2 mg/kg iv) were given; all
measurements were repeated after a 10- to 15-min stabilization period after
the first infusion (2 mg/kg) and after the final infusion (cumulative dose 8
mg/kg). Microspheres were administered for measurement of myocardial blood
flow during baseline conditions, during catecholamine infusion, and during the
DNP infusion.
Tissue preparation. With the use of a forceps precooled to –70°C, at the end of the experiment, an epicardial biopsy was taken from five normal, four LVH, and four CHF ventricles for subsequent analysis of ATP and creatine content using HPLC techniques (31). The heart was then fixed in 10% buffered formalin. The myocardium beneath the surface coil was sectioned into three transmural layers from epicardium to endocardium, weighed on an analytic balance, and placed into vials for counting of radioactivity. Similar specimens were obtained from the lateral and posterior LV wall to insure that the sample from beneath the surface coil was typical of the entire LV.
Data analysis. Numerical values for PCr and ATP during each
experimental condition were expressed as PCr/ATP.
was calculated from the measured blood flows and the difference in
O2 content between aortic and anterior coronary vein blood samples.
Hemodynamic data were measured from the chart recordings. Hemodynamic,
biochemical, and blood flow data were analyzed with one-way ANOVA with
replications. A value of P < 0.05 was required for significance.
When the ANOVA yielded a significant result, individual comparisons were made
using the method of Scheffé. Data are reported as means ±
SE.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Hemodynamic data. Hemodynamic data are shown in Table 2. At baseline, LV systolic pressure and the rate-pressure product (RPP) were significantly higher in hearts with aortic stenosis than in normal hearts (Table 2). LV end-diastolic pressure was significantly increased only in hearts with CHF. In all three groups, heart rate, LV systolic pressure, and RPP increased significantly during catecholamine stimulation. During high-dose DNP infusion, RPP increased significantly in the LVH and CHF animals but not in the normal group.
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Myocardial blood flow and oxygen consumption data. Mean myocardial
blood flow and the transmural distribution of perfusion were similar in
normal, LVH, and CHF hearts at baseline
(Table 3). Myocardial blood
flow and
increased significantly in all three groups during catecholamine infusion.
increased further in the normal and LVH groups during DNP infusion but not in
the CHF group.
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HEP measurements. HEP data are summarized in
Table 4. In normal animals,
31P spectra recorded during the control period were characterized
by high PCr/ATP. Basal PCr/ATP was significantly decreased in hearts with LVH
and further decreased in CHF hearts (Table
4, P < 0.05 vs. normal). Pi was too low to
identify at the signal-to-noise ratio of the spectra under basal conditions in
any group. Infusion of dopamine-dobutamine caused significant reductions of
PCr/ATP in normal and LVH hearts without a significant change in the already
low PCr/ATP in CHF hearts. Catecholamine infusion was associated with the
appearance of aPi resonance in all three groups of animals. As
shown in Table 4, the addition
of DNP to dobutamine-dopamine caused no further change of PCr/ATP in the
normal and LVH groups. However, in the animals with CHF, DNP caused a
significant further decrease of PCr/ATP, from 1.61 ± 0.06 to 1.47
± 0.11 (P < 0.05). In the normal animals, the addition of
DNP during catecholamine infusion caused no change in
Pi/PCr. In contrast, in both the LVH and CHF groups, the
addition of DNP resulted in significant increases of Pi/PCr
(Table 4). As shown in
Table 5, both ATP and total
creatine levels (chemically measured) were reduced in the CHF group, whereas
calculated [ADP] was significantly increased in both the LVH and CHF
groups.
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Mb- measurements. No Mb- resonance was
observed in any group under any of the experimental conditions, although
transient occlusion of the coronary artery supplying the area of myocardium
beneath the NMR coil consistently produced a large Mb- resonance.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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increased significantly in the normal and LVH groups but not in the CHF group;
and 3) DNP had no additional effect on PCr/ATP in the normal and LVH
groups but caused a significant further reduction of PCr/ATP in the CHF group.
These findings suggest that near-maximal oxidative capacity had been
approached during catecholamine stimulation in the CHF hearts but not in
normal hearts or hearts with compensated hypertrophy.
Swine pressure-overload hypertrophy model. In the present study, a
supravalvular aortic stenosis was applied in juvenile swine to produce an
initial pressure gradient of 70 mmHg across the constriction
(35). The animals subsequently
developed myocardial hypertrophy as the degree of aortic narrowing remained
fixed in the face of normal body growth. Approximately 40% of the animals
developed CHF as manifested by an increased LV end-diastolic pressure,
exercise intolerance, and ascites; the increase in LV/body weight was twice as
great in animals that developed CHF as in those with compensated LVH. With the
use of a similar but milder degree of aortic constriction in swine, Massie et
al. (19) found that a stenosis
that produced a 25-mmHg pressure gradient across the aortic narrowing resulted
in a 38% increase of LV mass in 6 mo with no evidence of heart failure in any
of the animals. The more severe aortic narrowing makes the present model
useful for study of the response of physiological and metabolic variables to
severe pressure overload and the evolution to overt CHF.
Previous evidence of bioenergetic abnormalities in hypertrophied and
failing myocardium. Myocardial PCr/ATP is decreased in patients
(22) and in large and small
animal models of LVH secondary to pressure and volume overload and
postinfarction LV remodeling
(11,
21,
23,
36,
37,
39). Furthermore,
abnormalities in oxidative phosphorylation have been described in in vitro
studies of failing myocardium
(6,
32). Consistent with these
observations, we (18,
24) recently reported that ATP
synthase and adenine nucleotide translocator (ANT) protein expression is
decreased in animals with CHF secondary to postinfarction remodeling or
pacing-induced heart failure. In swine with moderate pressure overload
produced by ascending aortic constriction, Massie et al.
(19) found that basal PCr/ATP
tended to be decreased in animals with LVH and that PCr/ATP decreased
significantly and similarly in normal and LVH hearts during the increased
cardiac work state produced by dobutamine infusion. They observed that animals
with LVH had greater glucose uptake during dobutamine stimulation; however, a
greater fraction of the glucose was oxidized in the LVH animals, indicated
that the preference for glucose in the LVH hearts was not the result of
ischemia. This finding is in agreement with the absence of Mb- in the
present study, indicating adequate oxygen availability. Thus the animals in
that study behaved similarly to the animals with compensated LVH in the
present study.
Do metabolic limitations constrain myocardial function? During
basal conditions, [ADP] was higher in the LVH and CHF hearts than in the
normal group. This indicates that the kinetic relationship between [ADP] and
the ATP synthesis rate (as indicated by
)
is altered in LVH and CHF myocardium
(37). Altered substrate
preference might contribute to the increased [ADP] in the overloaded hearts.
Hypertrophied and failing hearts demonstrate increased glucose utilization
(4); an increase in [ADP] has
been found in perfused hearts when glucose is the sole substrate
(9). Furthermore, swine hearts
with CHF secondary to postinfarction LV remodeling demonstrate decreased
expression of F1F0-ATPase and ANT1 proteins
(18,
24). The increased [ADP] may
reflect successful kinetic adaptation to the reduced ATP synthase and ANT1
protein expression or activity. However, the ability to increase contractile
performance and oxygen consumption in response to catecholamine stimulation in
the present study indicates that, under basal conditions, the hypertrophied
and failing hearts did have significant cytosolic and mitochondrial metabolic
reserve capacity to augment the ATP synthetic rate.
During catecholamine infusion,
approximately doubled in all groups. The animals with compensated LVH
tolerated the increased need for ATP synthesis during catecholamine
stimulation with no greater decrease of PCr/ATP than the normal hearts, and
the already low PCr/ATP in the CHF group did not decrease further. The normal
and functional responses of the CHF hearts to catecholamine stimulation were
surprising given the depressed adrenergic responsiveness generally observed in
failing hearts (25). It is
possible that there is less downregulation of -adrenergic receptor
pathways in the present swine pressure overload model than in CHF of other
etiologies. In addition, the aortic constriction appeared to contribute to the
increase of RPP, because, although aortic pressure did not increase in the CHF
hearts during catecholamine infusion (unlike the normal hearts in which aortic
pressure did increase), LV systolic pressure did increase significantly during
catecholamine infusion. In any event, the ability of the hypertrophied and
failing hearts to respond to catecholamine simulation was not less than that
of normal hearts.
Use of partial mitochondrial uncoupling to unmask a mitochondrial
functional abnormality. The mitochondrial uncoupling agent DNP was used
to examine whether mitochondrial oxidative capacity (proximal to ATP synthase)
was limited in LVH or CHF hearts during catecholamine stimulation. DNP
decreases the proton gradient across the mitochondrial inner membrane that is
required to support ATP synthesis. This results in compensatory augmentation
of mitochondrial carbon substrate and oxygen consumption to maintain the
proton gradient sufficient to sustain mitochondrial function
(15,
30). Thus DNP would be
expected to increase
and the rates of the supporting metabolic reactions that cause electrons to be
delivered to cytochrome oxidase if the rates of these reactions are not
already maximal. That is, an increase of
in response to DNP administration would indicate the presence of a functional
reserve proximal to ATP synthase. In the present study, DNP administered
during continuing catecholamine infusion elicited a 22% increase in
in normal hearts and in hearts with compensated LVH, indicating a reserve
oxidative capacity. Furthermore, the increased
produced by DNP did not tax oxygen delivery to the myocardium, because
myocardial Mb- remained below the level of detection. Taken together,
these data indicate that during DNP infusion, there was no limitation of
cytosolic oxygen availability and that the reserve oxidative capacity (i.e.,
beyond the level reached during catecholamine administration alone) was
present in normal hearts and in hearts with compensated hypertrophy.
In contrast to the normal hearts and hearts with compensated hypertrophy,
in the failing hearts administration of DNP during catecholamine infusion
caused no further increase in
.
Furthermore, DNP caused a significant decrease of the already low PCr/ATP. DNP
tended to increase RPP in all groups of animals, and this was significant in
the LVH and CHF groups during the high dose. This increase in cardiac work may
have contributed to the increased
in the normal and LVH groups as well as to the decrease in PCr/ATP in the
failing hearts. The failure of
to increase in response to DNP in the CHF group suggests that the maximal
capacity to utilize O2 had been approached during catecholamine
stimulation. The fall of PCr/ATP would be consistent with this view and
suggests that a compensatory increase of [ADP] occurred because respiration
was not able increase to compensate for the increased proton leak across the
inner mitochondrial membrane caused by DNP
(30). Alternatively, it is
possible that
failed to increase during DNP because the failing hearts had already become
partially uncoupled during the high workload produced by catecholamine
administration. Although the absolute increase in
in response to dobutamine-dopamine was greater in the CHF hearts, the relative
increase (compared with the baseline value) was similar in normal (+102%) and
CHF hearts (+105%) but tended to be less in LVH hearts (+70%). The mechanism
for the greater
per gram of myocardium during baseline conditions in the aortic banded animals
is uncertain, although we (1)
have previously observed that
was also significantly higher in dogs with LVH secondary to aortic banding
studied during awake conditions. It is likely that the increase in
during dobutamine-dopamine in the CHF hearts brought them closer to abolishing
their respiratory reserve compared with the normal hearts or the hearts with
compensated LVH.
Our findings are in agreement with previous in vitro studies that have
demonstrated that the maximal oxidative capacity of mitochondria
(33) or skinned fibers from
failing myocardium is decreased compared with normal myocardium
(32). However, the current
data indicate that such abnormalities are not sufficiently severe to constrain
in vivo performance at the moderately high work states induced by
catecholamine administration. Thus during basal conditions and with moderate
increases of cardiac workload bioenergetic abnormalities in failing myocardium
were not functionally limiting, and the decreased contractile performance was
likely the result of primary contractile abnormalities of the myocytes
(34) as well as an unfavorable
chamber geometry (13).
Therefore, during catecholamine administration, the rate of ATP expenditure,
rather than limitation of mitochondrial function, appeared to determine
in all groups of hearts. However, the DNP data suggest that maximal
had been approached in the CHF group during catecholamine infusion.
Calculations based on study of the oxidative capacity of isolated mitochondria
(18) suggest that the maximal
oxygen consumption capacity of normal swine myocardium should be 24.3
µmol · g wet wt–1 ·
min–1 or 54 ml · 100 g wet
wt–1 · min–1
(20). Because this value is
nearly twice the maximum
values achieved in the present study, a significant reduction of mitochondrial
capacity in the LVH group might not have been detected with the present
experimental protocol.
DNP causes increased local metabolic demands, which in turn result in metabolic vasodilation of the resistance vessels. In peripheral tissues, DNP causes a marked increase in oxygen extraction. However, in the porcine hearts in the present study, DNP caused no significant change in coronary venous oxygen tension, indicating no consistent change in myocardial oxygen extraction. If DNP had acted as a primary coronary vasodilator, then one would have expected decreased oxygen extraction by the heart with an increase in coronary venous oxygen tension. Conversely, if the increase in coronary flow was the result of an increase in oxygen demands, then one might have expected a decrease in coronary venous oxygen tension, because presumably an error signal would be required to elicit metabolic vasodilation. This did not occur. The possibility remains that DNP caused metabolic vasodilation but that oxygen was not the mediator of that response; rather, some other metabolic signal during DNP could have caused vasodilation. It is of interest that there is a difference in the response of coronary venous oxygen tension between dogs and swine during exercise. Whereas dogs show a marked decrease in coronary venous PO2 during exercise, swine do not, apparently because of feedforward control of the coronary circulation by the adrenergic nervous system (7). It is possible that adrenergic activation during DNP infusion similarly caused some degree of coronary vasodilation that prevented an increase in myocardial oxygen extraction in the present study.
The absence of myocardial myoglobin desaturation indicates that the
increased oxygen utilization during catecholamine infusion and DNP
administration did not exceed the ability to deliver oxygen. The inability to
detect Mb- with the 1H NMR technique indicates that myocyte
PO2 values were >15 mmHg, far above the
Michaelis-Menten constant value for O2 with respect to cytochrome
oxidase (38). However, the
values measured during maximal catecholamine stimulation are substantially
lower than the
levels that have been measured in normal hearts during heavy exercise
(1). Furthermore, DNP-induced
increases of
almost certainly underestimate "true" mitochondrial reserve
capacity (the maximum capacity to support ATP utilization under physiological
conditions). This is because decreases of the mitochondrial proton gradient
also compromise important mitochondrial functions other than ATP synthesis
such as maintenance of ion gradients; these functions are also required to
support ATP synthesis (26).
Consequently, DNP cannot be used estimate maximal
capacity (8). In intact tissues
including myocardium, DNP can decrease the proton gradient to the point that
the ATP synthesis rate required to support contractile and other cellular
functions cannot be maintained despite a substantial increase in
.
However, it is reasonable to assume that a significant increase of
induced by DNP does indicate the presence of a reserve mitochondrial oxidative
capacity so long as contractile function is maintained and HEP levels do not
markedly deteriorate.
In summary, during the high workload produced by catecholamine stimulation,
DNP was able to further increase
in compensated hypertrophied hearts, indicating a significant energy
generation reserve. Furthermore, the increase of
in response to DNP occurred with no reduction of PCr/ATP. These findings
support the view that primary abnormalities of oxidative ATP production did
not constrain contractile performance at moderately high workloads in hearts
with compensated pressure overload hypertrophy. In contrast, during
catecholamine stimulation in failing hearts, DNP failed to increase of
and caused a significant reduction of PCr/ATP. These findings suggest that the
capacity of some rate-limiting reaction(s) in the oxidative ATP synthetic
pathway may have been reached during the high workload produced by
catecholamine administration.
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DISCLOSURES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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S. Goffart, J.-C. von Kleist-Retzow, and R. J. Wiesner Regulation of mitochondrial proliferation in the heart: power-plant failure contributes to cardiac failure in hypertrophy Cardiovasc Res, November 1, 2004; 64(2): 198 - 207. [Abstract] [Full Text] [PDF]
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