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(Circulation. 1999;99:2565-2570.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Myocardial Dysfunction in Donor Hearts
A Possible Etiology
From Cardiothoracic Surgery (V.J.O., P.B.J.B., J.R.P., P.J.R.B., M.H.Y.) and Cardiac Medicine (S.E.H.), National Heart and Lung Institute at Imperial College School of Medicine, London, UK; Nephrology Laboratory (M.C.M.), Klinikum Essen, Essen, Germany; and Klinik III fur Innere Medizin (O.Z., M.B.), Universitat zu Köln, Germany.
 |
Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—Potential cardiac donors show various degrees of myocardial dysfunction, and the most severely affected hearts are unsuitable for transplantation. The cause of this acute heart failure is poorly understood. We investigated whether alterations in calcium-handling proteins, ß-adrenoceptor density, or the inhibitory G protein Gi
could account for this phenomenon in unused donor hearts (n=4 to 8). We
compared these with end-stage failing hearts (n=14 to 16) and
nonfailing hearts (n=3 to 12).
Methods and Results—Myocardial samples were obtained from
unused donor hearts displaying ejection fractions <30%. Both
trabeculae and isolated myocytes responded as poorly as
those from the group of failing hearts to increasing stimulation
frequency with regard to inotropic function in vitro. Immunodetectable
abundance of sarcoplasmic reticulum calcium-ATPase and sodium calcium
exchanger were greater (177%; P<0.01) and smaller
(29%; P<0.01), respectively, in the unused donor
hearts relative to the failing group, which suggests that alterations
of these proteins are not a common cause of contractile dysfunction in
the 2 groups. Myocytes from the unused donor group were desensitized to
isoprenaline to a similar degree as those from the failing heart group.
However, ß-adrenoceptor density was reduced in the failing
(P<0.001) but not in the unused donor heart group
(P=0.37) relative to the nonfailing heart group (n=5).
Gi activity was increased in samples from unused donor
and failing hearts relative to nonfailing hearts
(P<0.05).
Conclusions—Increased activity of the inhibitory G
protein Gi is a significant contributory factor for
impaired contractility in these acutely failing donor
hearts.
Key Words: transplantation • heart failure • proteins • receptors, adrenergic, beta • contractility
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The shortage of donor organs considerably limits the availability of heart transplantation and has led to the search for ways to increase the size of the donor pool. Myocardial dysfunction occurs to various degrees in all brain-dead organ donors, and we and others have found this to be so severe in
20% of cases that it
precludes the use of these hearts for transplantation.1
Because much of the early posttransplantation mortality is due to graft
failure, the use of such hearts is surrounded by uncertainty and
conjecture.
The present study was designed to examine the origin of myocardial
dysfunction in potential organ donors. Cellular mechanisms considered
important in end-stage heart failure were examined in a group of unused
donor hearts with ejection fractions <30%. Characteristically,
myocardium from end-stage failing hearts is slow to relax,
perhaps owing to reduced levels of expression of the sarcoplasmic
reticulum calcium-ATPase (SERCA2).2 Furthermore, end-stage
failing myocardium is desensitized to ß-agonists because
of ß-adrenoceptor (ß-AR) downregulation coupled with upregulation
of the inhibitory G protein
Gi.3 4 We have characterized the
contractile behavior of cells and trabeculae from unused
donor hearts and compared it with that seen in hearts with end-stage
failure. Myocardial samples were analyzed for abundance of the
key calcium-handling proteins SERCA2, sodium calcium exchanger (NCX),
and phospholamban (PLB). Finally, ß-AR density was assessed and
compared with that seen in both normal and failing myocardial tissue
samples, together with the expression of Gi.
Our data show that myocardial dysfunction in donor hearts is associated
with impaired contractile function in vitro, decreased ß-AR
sensitivity, and elevated Gi
activity.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Tissue Retrieval and Storage
Myocardium was obtained from Royal Brompton and Harefield Hospital CABG patients with good ventricular function (the nonfailing group, with ejection fractions [EFs] >60%) and those with moderate heart failure (New York Heart Association [NYHA] class II or III). Samples from end-stage heart failure (NYHA IV) were taken at the time of transplantation. The cause of all heart failure in these patients was either ischemic heart disease (IHD) or idiopathic dilated cardiomyopathy (DCM). In all cases, ventricular function was assessed angiographically. Ventricular function in potential cardiac donors was assessed by transesophageal echocardiography, with the transgastric short-axis area used as an assessment of fractional shortening and hence EF. Hearts from those individuals with EFs <30% coupled with poor hemodynamic parameters (blood pressure, left and right atrial pressures) were not used for transplantation but were retrieved normally (with ice-cold St Thomas cardioplegia solution 20 mL/kg) and used for homograft valve preparation and as a source of tissue for this study.
Samples from unused donor (UD) hearts were transported to the laboratory in ice-cold St Thomas cardioplegia solution. Tissue was divided into 3 portions that were either frozen in liquid N2 and stored at -80°C for later biochemical analysis, used to isolate myocytes as previously described,5 or used as a source of trabeculae for contraction measurements.
Ethical approval was obtained from the Royal Brompton and Harefield Hospital Ethical Committee, and informed written consent was obtained in all cases.
In Vitro Assessment of Contractile Function
Myocyte and trabeculae contractile responses were
assessed as previously described.5 6 Contraction of both
isolated myocytes and multicellular preparations was studied at 32°C
and either 2 mmol/L Ca2+ (for
trabeculae) or 2 to 10 mmol/L
Ca2+ (for myocytes). The effect of a range of
frequencies on contraction amplitude and postrest behavior was examined
after rest intervals of 10, 30, and 180 seconds. For isolated myocytes,
a concentration-response curve to isoproterenol was also
constructed.
Biochemical Analysis
Western blot analysis was performed on samples of
myocardium as described previously.7
ß-Adrenoceptors were identified by
[125I]iodocyanopindolol binding as previously
described8 with minor modifications. Briefly, cardiac
homogenates were centrifuged for 20 minutes at
50 000g, and the pellet was washed by
recentrifugation. After resuspension of the final
pellet in binding buffer (154 mmol/L NaCl, 10 mmol/L Tris, pH
7.4), aliquots of the membrane suspension were incubated in a total
volume of 250 µL for 90 minutes at 37°C. Incubations were
terminated by rapid vacuum filtration over Whatman GF/C filters, which
were washed with 20 mL of binding buffer. Nonspecific binding was
defined by 1 µmol/L CGP 12177. ß1- and
ß2-adrenoceptors were estimated from
competition experiments with the highly
ß1-selective antagonist CGP
20712A.
Gi activity was assessed by pertussis
toxin–induced [32P]ADP ribosylation and
standardized to both the amount of total protein and 5'-nucleotidase
activity as a membrane marker. The [32P]ADP
ribosylation of Gi by pertussis toxin was
performed for 14 hours at 4°C in a volume of 40 µL containing
100 mmol/L dithiothreitol, 2 mmol/L ATP, 1 mmol/L GTP,
50 mmol/L [32P]NAD (800 Ci/mmol), and 20
µg/mL pertussis toxin that had been activated by incubation
with 50 mmol/L dithiothreitol for 1 hour at 20°C before the
labeling reaction. Samples were subjected to SDS-PAGE (10% wt/vol
acrylamide and 16 cm total gel length). Gels were stained
with Coomassie blue and dried before autoradiography
was performed. Incorporated [32P]ADP ribose was
quantified by cutting out the bands from dried gels and by
scintillation counting.
Statistical Analysis
Significance was assessed on grouped data with either Student's
t test for unpaired data or an ANOVA where indicated. Data
from 1 to 3 cells for each patient were pooled before analysis
so that n values refer to patients. Values are expressed as
mean±SEM.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Transesophageal echocardiography was performed on 107 potential heart and heart-lung donors examined by the Royal Brompton and Harefield Hospital transplant team. Of these, 23 organs (21.5%) were not used for transplantation because of EFs <30% coupled with poor hemodynamic parameters, including elevated left atrial pressure, arterial blood pressure, right atrial pressure, and pulmonary artery pressure. In all cases, cardiovascular history and cardiovascular risk factors were negative, and there were no noted episodes of cardiac arrest. The clinical details of these patients are shown in the Table
.
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Force-Frequency Relationship Was Depressed in
Myocardium From UD Hearts
Normal myocardium maintains a positive Bowditch or
force-frequency relationship, whereas end-stage failing
myocardium exhibits a flat or negative Bowditch
response.9 Figure 1
summarizes the force-frequency relationships seen in
trabeculae preparations (Figure 1A) and isolated
myocytes (Figure 1B) from the UD group, along with end-stage
failing (F; both DCM and IHD) and nonfailing (NF)
myocardium. The force-frequency relationship in
trabeculae was indistinguishable between the F and UD
groups. Similarly, increasing the stimulation frequency failed to
increase the contraction amplitude of myocytes from either the UD or F
groups (Figure 1B); however, contraction amplitude was
significantly increased in myocytes from NF myocardium
(P<0.001; n=12). Analysis of the increase in
contraction from 0.1 to 1 Hz for the 3 groups differed significantly by
ANOVA (P=0.03).
|
) (n=16) and UD (
) hearts (n=8).
B, Force-frequency relationship in isolated myocytes prepared from NF
myocardium (
), end-stage failing myocardium
(F) (
), or UD myocardium (
Postrest Contraction Amplitude Was Increased in UD
Myocardium
Potentiation of the postrest contraction amplitude relative to
prerest levels is thought to reflect a gain of calcium in the
sarcoplasmic reticulum (SR) during quiescence.10 SR
function in myocardium of both the UD and F groups was
assessed by comparison of the amplitude of the first beat after a rest
period. We have previously shown that myocytes isolated from normal
myocardium tend to show postrest decay, whereas failing
myocardium exhibits postrest potentiation.11
Postrest amplitude from the UD group was examined, and the first beats
after different rest periods at 4 stimulation frequencies are
presented in Figure 2A. A
comparison between the postrest amplitude from the UD and F groups is
presented in Figure 2B. Myocardium from both
UD and F groups showed similar postrest potentiation (ANOVA;
P=0.184).
|
), 0.2 (
Beat Duration Was Increased in UD Myocardium
Myocyte beat duration was analyzed in terms of time to
peak contraction (TTP), time to 50% relaxation
(R50), and time to 90% relaxation
(R90). A comparison between cells from the UD
group (4 patients) and data gathered from the NF (20 patients) and F
(61 patients; both IHD and DCM) groups is shown in Figure 3A. TTP was similar in both the NF and UD
groups, both being significantly shorter than for cells from the F
group. However, relaxation times for the UD group were prolonged.
R50 values in myocytes from the UD group were
even longer than in those from the F group and were significantly
different from either the F or NF groups. R90
values were also prolonged, dramatically so in some myocytes. This
prolongation of relaxation, particularly the second phase, is shown in
representative traces in Figure 3B.
|
ß-AR Sensitivity Was Decreased in UD Myocardium
Responses of isolated myocytes from UD, F, and NF groups to
isoproterenol were compared (Figure 4).
Myocytes from the UD group showed a similar degree of ß-AR
desensitization to that seen in the moderately failing groups
investigated previously, corresponding to cells from patients with NYHA
class II or III failure.
|
), and 11 hearts from patients in end-stage heart failure (NYHA IV)
(
Key Calcium-Handling Protein Expression in UD Was Significantly
Different From End-Stage Failing Myocardium
When Western blot analysis was used, expression of SERCA2
was found to be significantly higher in the UD group than in the F
group (P<0.01) whereas NCX was significantly lower
(P<0.01). PLB levels were also higher in the UD group
relative to the F group (60%; P<0.05; data not shown).
Protein levels are shown in Figure 5, with the F group divided into IHD and DCM. The relationship between the
UD and F groups was similar to that previously reported between normal
and failing myocardium for these
proteins.12 13
|
ß-AR Number Was Unchanged in UD Myocardium
Because of the functional ß-AR desensitization seen in the UD
group, ß-AR number was measured in myocardial samples from this
group. Measurements were compared with the NF and F (DCM and IHD)
groups. ß-AR number was not significantly different between the UD
and NF groups but was decreased in the F group, in agreement with
previous results14 (Figure 6A; P<0.001).
|
Inhibitory G-Protein (Gi) Activity Is
Increased in UD Myocardium
Increased activity of the inhibitory G-protein subunit
Gi has been demonstrated in end-stage heart
failure.15 We therefore measured
Gi activity in the NF, F (both DCM and IHD),
and UD groups. The IHD group showed significantly higher
Gi activity than the NF group
(P<0.01; Figure 6B
), as previously
described,16 yet the DCM group did not show a
significant elevation. Gi activity in the UD
group was similar to that in the IHD group and significantly higher
than in the NF group (P<0.02; Figure 6B).
|
Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The major finding of this study is that myocardial dysfunction seen in brain-dead organ donors appears to be unrelated to alterations in calcium-handling protein levels or ß-AR receptor density. However, we detected a significant elevation in the level of the inhibitory G protein Gi
. Characteristic changes in the expression of SERCA2, NCX, and PLB have been reported in human heart failure. For example, SERCA2 mRNA has been found to be reduced in studies of human failing myocardium compared with nonfailing myocardium.17 18 19 However, some studies report a decrease at the protein level, whereas others show no change in expression.18 19 A significant correlation has been demonstrated relating the abundance of SERCA2 protein and myocardial function as assessed by the force-frequency relationship.13 19 The majority of reports find no change in protein levels of PLB between failing and nonfailing myocardium.19 20 Studer et al12 found that mRNA and protein levels of NCX were significantly increased in failing myocardium, a result recently confirmed by Flesch et al.21 Correspondingly, the level of activity of the NCX is increased in failing compared with nonfailing myocardium.22 Because both NCX and SERCA2 act primarily to remove calcium from the cytosol, this increase in NCX activity could theoretically compensate for the reduced SERCA2 activity. It has been observed that epicardial muscle strips from patients in whom NCX is upregulated at the same time that SERCA2 is downregulated have better preserved function than those patients in whom SERCA2 is decreased and NCX unchanged.2
Our data demonstrate that hearts with impaired systolic and diastolic function, as assessed by echocardiography, also demonstrate impaired function in vitro (slow relaxation and poor frequency response). However, the levels of SERCA2 and NCX are significantly different from those seen in end-stage failing myocardium and more closely resemble those seen in normal heart. This is evidence against a link between the alteration in calcium-handling protein levels and loss of the frequency response or impairment of relaxation. Additional support for the possibility of uncoupling the force-frequency relationship from alterations in calcium-handling proteins comes from studies showing an abnormal force-frequency relationship in dilated cardiomyopathy without a decrease in the level of SERCA2 expression but with a reduced SERCA2 Vmax.23
The loss of function of the catecholamine signaling pathway
is well known to accompany end-stage heart failure, either as a result
of altered receptor density, subtype alterations, or uncoupling from
the appropriate signal transduction pathway. That such a mechanism
could contribute to impaired myocardial performance in acute
failure, as seen in the UD group, was suggested by our finding that
isolated myocytes were less responsive to the ß-agonist
isoproterenol. However, ß-AR downregulation did not occur, which
suggests that it is the signal transduction pathway coupling the
receptors to the contractile apparatus that is impaired.
Impaired myocardial adenylate cyclase activity from
brain-dead organ donors has been reported previously in both adult
humans24 and pediatric animal models.25 In
the present study, myocardial samples from the UD group had
significantly elevated levels of Gi activity
compared with normal myocardium, with values comparable to
those found in end-stage heart failure. It is likely that this accounts
for the decrease in ß-AR sensitivity.
Increased Gi activity may also provide a link
to explain decreased function in the presence of normal SERCA2 levels.
Exposure of rats to isoproterenol causes an increase in
Gi,26 and treatment of neonatal
myocyte cultures with norepinephrine both decreases basal
cAMP and increases Gi.27 Hence,
increasing Gi may act to reduce the tonic
activity of SERCA2 by decreasing basal cAMP. It may be that
Gi upregulation is an acute response in heart
failure, followed in the long term by downregulation in ß-AR
density.
It could also be considered that Gi plays a
more fundamental role in the induction of heart failure. A provisional
study28 reports that transgenic mice with increased
Gi levels develop a form of dilated
cardiomyopathy. Of particular relevance to the
present study is the finding that Gi
levels were elevated by 225% in patients who died of
"catecholamine refractory" cardiogenic shock after
myocardial infarction.3 It may therefore be that a similar
pathophysiological mechanism is responsible for
both cardiogenic shock and brain-death–induced acute heart failure and
that the 2 conditions are, in clinical terms, the same entity.
Conclusions
We have demonstrated that myocardial dysfunction seen in unused
donor hearts is associated with significantly elevated levels of the
inhibitory G protein Gi. Although
the function of myocardial tissue from these subjects was impaired,
protein levels of SERCA2 and NCX and density of ß-ARs were distinctly
different from failing hearts and resembled those of nonfailing tissue.
The increase in Gi could play a central role
not only in ß-AR desensitization but also in fundamental changes in
muscle contractility. These observations, coupled with
our previous finding that inactivation of Gi
with pertussis toxin restores ß-AR function in myocytes from human
hearts with end-stage failure,29 may be valuable in the
design of therapeutic strategies to restore myocardial function in
these patients and so increase the volume of this valuable
resource.
|
Acknowledgments |
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This work was supported in part by the Wellcome Trust (Dr Owen), the Medical Research Council (Dr Burton), the Deutsche Forschungsgemeinschaft (Drs Böhm and Zolk), and The British Heart Foundation (Drs Owen, Barton, and Yacoub).
|
Footnotes |
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Reprint requests to Dr Virginia J. Owen, Cardiothoracic Surgery, National Heart and Lung Institute at Imperial College School of Medicine, Dovehouse St, London, SW3 6LY, UK.
Received September 18, 1998; revision received February 1, 1999; accepted February 12, 1999.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Hosenpud JD, Novick RJ, Breen TJ, Kedem J, Daily P. The registry of the international society for heart and lung transplantation: 12th official report: 1995. J Heart Lung Transplant. 1995;14:805–815.[Medline] [Order article via Infotrieve]
2. Hasenfuss G, Preuss M, Lennart S, Prestle J, Meyer M, Just H. Relationship between diastolic function and protein levels of sodium-calcium exchanger in end-stage failing human hearts. Circulation. 1996;94(suppl I):I-433. Abstract.
3.
Bohm M, Kirchmayr R, Erdmann E. Myocardial
Gi-protein levels in patients with hypertensive cardiac
hypertrophy, ischemic heart disease and cardiogenic
shock. Cardiovasc Res. 1995;30:611–618.[Medline]
[Order article via Infotrieve]
4. Bohm M, Flesch M, Schnabel P. Role of G-proteins in altered beta-adrenergic responsiveness in the failing and hypertrophied myocardium. Basic Res Cardiol. 1996;91(suppl 2):47–51.
5.
Davies CH, Davia K, Bennett JG, Pepper JR,
Poole-Wilson PA, Harding SE. Reduced contraction and altered frequency
response of isolated ventricular myocytes from patients
with heart failure. Circulation. 1995;92:2540–2549.
6. Harding SE, Gurden JM, Poole-Wilson PA. A comparison of contractile function between papillary muscles and isolated myocytes from the same human hearts. Cardioscience. 1991;2:141–146.[Medline] [Order article via Infotrieve]
7.
Burton PBJ, Yacoub MH, Barton PJR. Cyclin dependent
kinase inhibitor expression during the development of human
heart failure: a comparison with fetal development. Eur
Heart J. 1999;20:604–611.
8. Brodde OE, Zerkowski HR, Doetsch N, Motomura S, Khamssi M. Myocardial beta-adrenoceptor changes in heart failure: concomitant reduction in beta 1- and beta 2-adrenoceptor function related to the degree of heart failure in patients with mitral valve disease. J Am Coll Cardiol. 1989;14:323–331.[Abstract]
9.
Mulieri LA, Hasenfuss G, Leavitt BJ, Allen PD, Alpert
NR. Altered myocardial force-frequency relation in human heart failure.
Circulation. 1992;85:1743–1750.
10. Lewartowski B, Zdanowski K. Net Ca2+ influx and sarcoplasmic reticulum Ca2+ uptake in resting single myocytes of the rat heart: comparison with guinea-pig. J Mol Cell Cardiol. 1990;22:1221–1229.[Medline] [Order article via Infotrieve]
11. Davia K, Poole-Wilson PA, Harding SE. Effect of digoxigenin on the post-rest contraction amplitude in myocytes from failing and non-failing human ventricle. Eur Heart J. 1996;17(suppl):325. Abstract.
12.
Studer R, Reinecke H, Bilger J, Eschenhagen T, Bohm M,
Hasenfuss G, Just H, Holtz J, Drexler H. Gene expression of the cardiac
Na(+)-Ca2+ exchanger in
end-stage human heart failure. Circ Res. 1994;75:443–453.
13.
Hasenfuss G, Reinecke H, Studer R, Meyer M, Pieske B,
Holtz J, Holubarsch C, Posival H, Just H, Drexler H. Relation between
myocardial function and expression of sarcoplasmic reticulum
Ca(2+)-ATPase in failing and nonfailing human
myocardium. Circ Res. 1994;75:434–442.
14.
Bristow MR, Anderson FL, Port JD, Skerl L, Hershberger
RE, Larrabee P, O'Connell JB, Renlund DG, Volkman K, Murray J, Feldman
AM. Differences in ß-adrenergic neuroeffector mechanisms in
ischemic versus dilated cardiomyopathy.
Circulation. 1991;84:1024–1039.
15. Feldman AM, Cates AE, Veazey WB, Hershberger RE, Bristow MR, Baughman KL, Baumgartner WA, Van Dop C. Increase of the 40,000-mol wt pertussis toxin substrate (G protein) in the failing human heart. J Clin Invest. 1988;82:189–197.
16.
Bohm M, Eschenhagen T, Gierschik P, Larisch K, Lensche
H, Mende U, Schmitz W, Schnabel P, Scholz H, Steinfath M, Erdmann E.
Radioimmunochemical quantification of Gi in right and left
ventricles from patients with ischemic and dilated
cardiomyopathy and predominant left
ventricular failure. J Mol Cell Cardiol. 1994;26:133–149.[Medline]
[Order article via Infotrieve]
17.
Arai M, Alpert NR, MacLennan DH, Barton P, Periasamy M.
Alterations in sarcoplasmic reticulum gene expression in human heart
failure: a possible mechanism for alterations in systolic and
diastolic properties of the failing myocardium.
Circ Res. 1993;72:463–469.
18. Schwinger RHG, Bohm M, Bavendiek U, Karczewski P, Flesch M, Krause E-G, Erdmann E. Reduced mRNA-levels and Ca2+-ATPase activity but unchanged protein levels of SERCA II in myocardium from patients with dilated cardiomyopathy compared to non-failing tissue. Eur Heart J. 1995;16(suppl):455. Abstract.
19. Linck B, Boknik P, Eschenhagen T, Muller FU, Neumann J, Nose M, Jones LR, Schmitz W, Scholz H. Messenger RNA expression and immunological quantification of phospholamban and SR-Ca(2+)-ATPase in failing and nonfailing human hearts. Cardiovasc Res. 1996;31:625–632.[Medline] [Order article via Infotrieve]
20.
Movsesian M, Karimi M, Green K, Jones J.
Ca2+ transporting ATPase, phospholamban and
calsequestrin in nonfailing and failing human myocardium.
Circulation. 1994;90:653–657.
21.
Flesch M, Schwinger RH, Schiffer F, Frank K, Sudkamp M,
Kuhn-Regnier F, Arnold G, Bohm M. Evidence for functional relevance of
an enhanced expression of the
Na(+)-Ca2+ exchanger in
failing human myocardium. Circulation. 1996;94:992–1002.
22. Reinecke H, Studer R, Vetter R, Holtz J, Drexler H. Cardiac Na+/Ca2+ exchange activity in patients with end-stage heart failure. Cardiovasc Res. 1996;31:48–54.[Medline] [Order article via Infotrieve]
23. Muench G, Bolck B, Brixius K, Schwinger RHG. Unchanged protein expression of sarcoplasmic reticulum Ca2+ ATPase, phospholamban, and calsequestrin in terminally failing human myocardium. Circulation. 1997;96(suppl I):I-238. Abstract.
24.
White M, Wiechmann RJ, Roden RL, Hagan MB, Wollmering
MM, Port JD, Hammond E, Abraham WT, Wolfel EE, Lindenfeld J, Fullerton
D, Bristow MR. Cardiac ß-adrenergic neuroeffector systems in
acute myocardial dysfunction related to brain injury: evidence for
catecholamine-mediated myocardial damage.
Circulation. 1995;92:2183–2189.
25. Harding SE, Davia K, Davies CH, del Monte F, Money-Kyrle AR, Poole-Wilson PA. From overload to failure: what happens inside the myocyte. Ann Med. 1998;30:14–23.
26. Eschenhagen T, Mende U, Diederich M, Nose M, Schmitz W, Scholz H, Schulte am Esch J, Warnholtz A, Schafer H. Long term beta-adrenoceptor-mediated up-regulation of Gi alpha and G(o) alpha mRNA levels and pertussis toxin-sensitive guanine nucleotide-binding proteins in rat heart. Mol Pharmacol. 1992;42:773–783.[Abstract]
27. Reithmann C, Gierschik P, Sidiropoulos D, Werdan K, Jakobs KH. Mechanism of noradrenaline-induced heterologous desensitisation of adenylate cyclase stimulation in rat heart muscle cells: increase in the level of inhibitory G-protein alpha-subunits. Eur J Pharmacol. 1989;172:211–221.[Medline] [Order article via Infotrieve]
28. Baker AJ, Redfern C, Figueredo VM, Keung EC, Camacho SA, Conklin BR. Role of G protein signaling in cardiomyopathy: physiologic measurements from transgenic mouse hearts. Biophys J. 1998;74:A353. Abstract.
29. Brown LA, Harding SE. The effect of pertussis toxin on ß-adrenoceptor responses in isolated cardiac myocytes from noradrenaline-treated guinea-pigs and patients with cardiac failure. Br J Pharmacol. 1992;106:115–122.[Medline] [Order article via Infotrieve]
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 C. M.N. Terracciano, K. D. Philipson, and K. T. MacLeod Overexpression of the Na+/Ca2+ exchanger and inhibition of the sarcoplasmic reticulum Ca2+-ATPase in ventricular myocytes from transgenic mice Cardiovasc Res, January 1, 2001; 49(1): 38 - 47. [Abstract] [Full Text] [PDF]
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 H. Yokoyama, S. Gunasegaram, S. E. Harding, and M. Avkiran Sarcolemmal Na+/H+ exchanger activity and expression in human ventricular myocardium J. Am. Coll. Cardiol., August 1, 2000; 36(2): 534 - 540. [Abstract] [Full Text] [PDF]
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E. J. Birks, V. J. Owen, P. B. J. Burton, A. E. Bishop, N. R. Banner, A. Khaghani, J. M. Polak, and M. H. Yacoub Tumor Necrosis Factor-{alpha} Is Expressed in Donor Heart and Predicts Right Ventricular Failure After Human Heart Transplantation Circulation, July 18, 2000; 102(3): 326 - 331. [Abstract] [Full Text] [PDF]
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