(Circulation. 2000;102:III-352.)
© 2000 American Heart Association, Inc.
Myocardial Protection and Vascular Biology |
Elevated Tumor Necrosis Factor-
and Interleukin-6 in Myocardium and Serum of Malfunctioning Donor Hearts
From the National Heart and Lung Institute at Imperial College School of Medicine, Royal Brompton and Harefield Hospital, Harefield, Middlesex, UK.
Correspondence to Magdi Yacoub, FRS, Professor of Cardiothoracic Surgery, Heart Science Centre, Royal Brompton and Harefield Hospital, Harefield, Middlesex UB9 6JH, UK.
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Abstract |
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Background—Myocardial dysfunction is a common and important problem in donor hearts. The mechanisms responsible remain unclear. We have studied the cytokines tumor necrosis factor (TNF)-
and interleukin-6 (IL-6) in the
myocardium and serum from donors with myocardial
dysfunction (unused donors) and compared them with donors with good
ventricular function (used donors) and patients with
advanced heart failure (HF).
Methods and Results—Clinical details and ventricular
function were assessed in 46 donors (31 used, 15 unused). Real-time
reverse transcription–polymerase chain reaction, Western blotting, and
immunocytochemistry were performed on myocardium and
immunoassays on serum. TNF- mRNA was 1.6-fold higher in unused than
in used donors (P<0.005) and 1.74-fold higher than in
36 patients with HF. IL-6 mRNA was 2.4-fold higher in unused than in
used donors (P<0.0001) and 4.67-fold higher than in HF
(P<0.0001). Western blotting showed higher TNF- in
unused (218.3±6.4, n=4 versus 187.3±5.4, n=3 OD units) than used
donors (P<0.05). TNF- expression was localized to
cardiac myocytes. Serum TNF- was higher in unused (8.72±1.3 pg/mL,
n=13) than in used (6.12±0.8 pg/mL, n=25, P<0.05)
donors and HF (4.0±0.4 pg/mL, n=17, P<0.005). Serum
TNF- receptors did not differ between unused (4.3±0.8 and 8.6±1.6
ng/mL, n=10) and used (3.5±0.4 and 6.5±1.1 ng/mL, n=24) donors. There
was a trend for higher serum IL-6 in unused (16.5±2.9 pg/mL, n=9)
compared with used (13.9±1.6 pg/mL, n=26, P=NS)
donors.
Conclusions—This study documented an increase in the expression
of TNF- and IL-6 in the myocardium of all donor hearts
that was more marked in the dysfunctional (unused) donor hearts. This
was accompanied by similar changes in the serum. This might have
important therapeutic implications.
Key Words: transplantation • myocardium • molecular biology
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Introduction |
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Myocardial dysfunction in the donor heart is a common problem and is so severe as to preclude its use for transplantation in 20% of cases. Brain death has been shown to result in various degrees of myocardial dysfunction,1 but the mechanisms remain poorly understood. Trabeculae and isolated myocytes from dysfunctional donors demonstrate a slowed relaxation and a poor force-frequency response in vitro comparable to that of hearts from patients with advanced heart failure.2
Patients with chronic heart failure due to a variety of causes have
been found to have elevated expression of proinflammatory
cytokines including tumor necrosis factor (TNF)- both in the
serum and myocardium.3 4 5 6 7 TNF- expression
has been demonstrated6 7 in the ventricles of patients
with dilated cardiomyopathy, where it was seen in
cardiac myocytes, endothelial cells, and in the
vascular smooth muscle cells of intramyocardial blood vessels.
Exogenous and endogenous TNF- have been shown to produce
myocardial depression and hemodynamic effects both in
in vitro and in vivo models.4 5 8 9 Interleukin 6 (IL-6)
is also elevated in patients with heart failure,3 5 10 11
and raised levels correlate with decreasing functional class, low
ejection fraction, high right atrial pressures, and poor
prognosis.5 10
The possible role of cytokines in producing donor dysfunction
in humans has not been explored. In this study, we compare TNF- and
IL-6 expression in the myocardium together with circulating
levels of TNF- and its receptors, TNFR1 and TNFR2, and IL-6 in
donors exhibiting myocardial dysfunction to donor hearts with good
ventricular function used for transplantation. In an
attempt to put these findings into perspective, we have also included
myocardium from patients with advanced heart failure and
serum from normal control subjects.
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Methods |
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Donors
The protocol for this study was approved by the local ethics committee. Donor hearts were assessed by transesophageal echocardiography before retrieval. The transgastric short-axis area was used to assess fractional shortening and hence ejection fraction (EF). Donors with an EF <30% coupled with 2 of the following poor hemodynamic parameters were judged unsuitable for transplantation (unused donors): mean blood pressure <50 mm Hg, mean left atrial pressure >14, inotropic support (norepinephrine and/or epinephrine) >0.4 µg · kg-1 · min-1 necessary to maintain systolic blood pressure >90 mm Hg. This group was compared with a group of donors with good ventricular function used for transplantation. Donor clinical details, cause of death, period of ventilation, and any evidence of systemic infection were recorded. Infection in the donor was defined as a raised white cell count combined with either pyrexia or evidence of consolidation on chest radiography.
Unused Donor Hearts
Donor hearts unused for transplantation because of poor
myocardial function (n=15) were retrieved normally after cold
crystalloid cardioplegia with 20 mL/kg St Thomas cardioplegic
solution. Left ventricular samples were taken from the
apical area and transported to the laboratory in cardioplegia, where
they were stored at -80°C. The mean time of transport to the
laboratory was 137.9±12.6 minutes. Causes of death were
subarachnoid hemorrhage (6), road traffic accident (4),
intracranial bleed (2), epileptic seizure (1), meningitis (1), and
astrocytoma (1). Clinical details are shown in the
Table
.
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Used Donor Hearts
Ventricular endomyocardial
biopsies were obtained immediately before implantation from 31 donors
used for transplantation during the same period, frozen in liquid
nitrogen, and stored at -80°C. The donor heart was preserved by
infusion of St Thomas’ solution at 4°C. Mean ischemia
time was 163±10.2 minutes. Causes of death were subarachnoid
hemorrhage (13), road traffic accident (8), intracranial bleed
(4), asthma (1), astrocytoma (1), and carbon monoxide poisoning (1),
and 3 were domino hearts from patients undergoing heart-lung
transplantation for cystic fibrosis. All had normal ECGs. Clinical
details are shown in the Table
. Hearts were reassessed by
transthoracic echocardiography 1 week
after transplantation, and all had good ventricular
function (mean EF 72.8±1.4%).
Heart Failure
Left ventricular samples were obtained from 36
patients with advanced heart failure undergoing heart transplantation.
Thirty were men and 6 were women. Mean age was 46±3.4 years. Diagnosis
was dilated cardiomyopathy (18), ischemic
heart disease (15), postpartum cardiomyopathy (2),
and myocarditis (1). New York Heart Association class was III in 28 and
IV in 8. Mean fractional shortening was 13.0±1.2%.
Serum
Blood was taken from 26 of the used and 13 of the unused donors
immediately before retrieval. Blood was also taken from 17 of the
advanced heart failure patients before transplantation and from 8
normal control subjects (5 men and 3 women, 44.2±3.2 years of age).
Blood was spun within 4 hours of collection at 2500 rpm for 10 minutes,
and the serum supernatant stored at -40°C for further
analysis.
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Methods |
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Real-Time Quantitative Reverse Transcription–Polymerase Chain Reaction
TNF-
and IL-6 mRNA were detected by polymerase chain reaction
(PCR) amplification and quantified by 5' nuclease assay with
fluorescent-labeled TaqMan probes analyzed with the use
of real-time quantitative PCR as follows. Total RNA was extracted with the Qiagen RNeasy minicolumn procedure and eluted in diethylpyrocarbonate-treated dH2O, following the manufacturer’s instructions. RNA quality and quantity was assessed by EtBr-agarose gel electrophoresis and by relative absorbance at 260 nm versus 280 nm. cDNA was synthesized from 150 ng of total RNA in a volume of 10 µL with the PE Biosystems reverse transcriptase kit (Cat No. N8080234) with random hexamer primers. Reactions were diluted to 100 µL with sterile dH2O and stored at -20°C.
Primers and TaqMan probe for human IL-6 were designed with the use of the Primer Express Software (PE Biosystems) from published mRNA sequence (EMBL/GenBank accession No. M54894) with flanking primers located on separate exons giving an amplicon size of 96 bp and with the TaqMan probe straddling the exon-exon junction: Forward primer (Tm=58°C) 5'-TGACAAACAAATTCGGTACATCCT-3', reverse primer (Tm=60°C)5'-AGTGCCTCTTTGCTGCTTTCAC-3', TaqMan probe (Tm=68°C)5'-TTACTCTTGTTACATGTCTCCTTT-CTCAGGGCTG-3'. Internal control 18S rRNA primers and TaqMan probe were provided as a preoptimized kit (Cat No. 4310893E).
Primer and TaqMan probe for the analysis of TNF- message
were designed, synthesized, and optimized by Perkin-Elmer and provided
as a preoptimized kit (Cat No. 4308251S). PCR reactions were performed
with the use of an ABI-prism 7700 sequence detector. PCR amplifications
were performed in a 25-mL volume containing 2.5 mL cDNA template in 2x
PCR Master Mix (PE Biosystems) at 50°C for 2 minutes, 95°C for 10
minutes followed by 40 cycles of 95°C for 15 seconds, and 60°C for
1 minute. Each sample was analyzed in duplicate. Results were
analyzed with the use of Sequence Detection Software (PE
Biosystems), and the level of expression of TNF- and IL-6 mRNA were
normalized to 18S rRNA, as outlined in User Bulletin No. 2, provided by
Perkin-Elmer.
Western Blot Analysis
Total protein extracts were prepared by
homogenizing myocardial biopsies in lysis buffer (1%
SDS, 1 mmol/L phenymethylsulfonylflouride, 10 µg ·
mL-1 aprotinin, and 10
µg · mL-1
leupeptin). Protein (40 µg per sample) was mixed with sample buffer
and loaded onto a 12.5% SDS-polyacrylamide gel. After
electrophoresis, proteins were transferred onto Hybond-C super
nitrocellulose membranes. Membranes were immersed in PBS-Tween 20 and
5% milk protein overnight at 4°C to block nonspecific binding. An
affinity-purified TNF- polyclonal antibody (Santa-Cruz
Biotechnology), diluted 1:500 (vol/vol) in PBS-T/5% milk protein, was
added to the membranes for 60 minutes. After washing, membranes were
incubated with a horseradish peroxidase–conjugated rabbit anti-goat
secondary antibody (DAKO) diluted 1:1000 (vol/vol) in PBS-T/35% milk
protein for 1 hour. The immunoreactive bands were visualized with the
use of Amersham enhanced chemiluminescence reagents and were scanned
with Image Analysis 1000 software (Alpha Innotech).
Immunocytochemistry
Immunocytochemistry was performed on formalin-fixed
paraffin-embedded sections to localize the cell type producing TNF-.
The avidin-biotin-peroxidase complex method was used.
Endogenous peroxidase was blocked with a solution of 0.03%
(vol/vol) hydrogen peroxide in methanol for 20 minutes. After
incubation with normal goat serum (1:30, 30 minutes), sections were
incubated overnight at 4°C with primary rabbit antibodies to TNF-
(Antigenex America Inc) diluted 1:100. Immunoreaction sites were
visualized with the use of the appropriate biotinylated secondary
antibodies and the avidin-biotin-peroxidase complex procedure (Vector
Labs). Peroxidase activity was revealed with a solution of
diaminobenzidine as chromogen with 0.2% (vol/vol) hydrogen peroxide in
PBS to produce a brown reaction product and sections counterstained
with Harris’ hematoxylin. Controls consisted of replacement of primary
antibodies with nonimmune rabbit serum.
Serum Immunoassay
Measurements of TNF-, its receptors TNF R1 and TNF R2, and
IL-6 were performed with commercially available immunoassay kits
(Quantikine HS, R & D Systems).
Statistical Analysis
Variables are expressed as mean±SEM. Significance was
assessed on grouped data with either the Student’s t test
or the nonparametric Mann-Whitney U test.
Fisher’s exact test was used to compare some of the clinical
variables. A value of P<0.05 was considered
significant.
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Results |
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Myocardium
TNF-
mRNATNF-
mRNA was measured in myocardial samples relative to 18S
ribosomal RNA (Figure 1). TNF-
mRNA expression in the 15 unused donors was 1.6-fold higher than in the
31 donors used for transplantation (P<0.005, Figure 2A). TNF- mRNA in the 15 unused donors
was also 1.74-fold higher than in the 36 patients with advanced heart
failure (P<0.001, Figure 2A). TNF- mRNA levels in
the used donor group were similar to levels in advanced heart failure
(1.09-fold, P=NS).
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TNF mRNA levels were not influenced by donor sex, cause of death, central venous pressure, the presence of infection in the donor, or ischemia time. In addition TNF, mRNA levels were not influenced by the number of inotropes used (1, 2, or 3) or the use of norepinephrine.
IL-6 mRNA
IL-6 mRNA expression was 2.4-fold higher in the unused donors than
in donors used for transplantation (P<0.0001, Figure 1B). IL-6 mRNA in the unused donors was 4.67-fold higher than in
the 36 patients with advanced heart failure (P<0.0001,
Figure 1). IL-6 mRNA levels in the used donor group were
1.96-fold higher than in advanced heart failure
(P<0.0001).
IL-6 mRNA levels were not influenced by donor sex, the presence of infection in the donor, or ischemic time but correlated with the quantity of inotropes used (levels being 3.18-fold in donors with 1 inotrope compared with those with none, P<0.0001, and 1.58-fold with 2 inotropes compared with 1, P<0.0001). IL-6 levels were 1.5-fold higher in those receiving norepinephrine compared with those not receiving (P<0.005).
TNF- Protein Expression by Western Blotting
TNF- expression was significantly higher in specimens examined
from unused donor hearts (mean 218.3±6.4 OD units, n=3) compared with
donor hearts used for transplantation (187.3±5.4 OD units, n=4,
P<0.05).
TNF- Immunocytochemistry
TNF- was strongly expressed in unused donor hearts (Figure 3, top) compared with used donor hearts
(Figure 3, bottom). TNF- was immunolocalized to cardiac
myocytes and was not expressed in endothelial cells and
only in occasional vascular smooth muscle cells.
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Serum
Serum TNF-
Serum TNF- was significantly higher in 13 unused donors
(8.72±1.3 pg/mL) compared with 25 used donors (6.12±0.8 pg/mL,
P<0.05, Figure 4). Serum
TNF- in both unused and used donors was significantly higher than in
8 normal subjects (2.58±0.45 pg/mL, P<0.0001 for unused
and P<0.001 for used donors). Serum TNF- in both donor
groups was also significantly higher than in advanced heart failure
(4.0±0.4 pg/mL, n=17, P<0.005 for unused and
P<0.05 for used donors). As expected, serum TNF- in
patients with advanced heart failure was higher than in normal subjects
(P<0.05).
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Serum TNFR1
There was no significant difference between serum TNFR1 levels in
unused (4.3±0.8 ng/mL, n=10) and used donors (3.5±0.4 ng/mL, n=24,
Figure 5A). There was also no significant
difference between serum TNFR1 levels in used (3.5±0.4
ng/mL, n=24) and unused (4.3±0.8 ng/mL, n=10) donors than
in heart failure (2.8±0.3 ng/mL, n=17, P=NS for both).
TNFR1 levels were higher in both unused and used donors and in patients
with heart failure than in normal subjects (1.1±0.4 ng/mL, n=8;
P<0.0001, P<0.0005, and P=0.0001,
respectively).
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Serum TNFR2
Serum TNFR2 levels were significantly higher in patients with
heart failure (9.0±0.8 ng/mL, n=17) than in normal subjects (4.7±0.5
ng/mL, n=8, P<0.005) but were not significantly higher in
either used (6.5±1.1 ng/mL, n=24) or unused (8.6±1.6 ng/mL, n=10)
donors than in normal subjects. There was no difference between TNFR2
in unused (8.6±1.6 ng/mL, n=10) and used (6.5±1.1 ng/mL, n=24) donors
(Figure 5B). TNFR2 levels were lower in used donors than in
patients with heart failure (P<0.01). TNFR2 levels were
nonsignificantly lower in unused donors than in patients with heart
failure.
Serum IL-6
There was a trend for higher serum IL-6 in unused (16.5±2.9
pg/mL, n=9) compared with used (13.9±1.6 pg/mL, n=26) donors (Figure 6) and in both unused and used donors
compared with patients with heart failure (12.7±2.6 pg/mL, n=17).
Serum IL-6 levels were significantly higher in unused (16.5±2.9 pg/mL,
n=9) and used (13.9±1.6 pg/mL, n=26) donors compared with normal
subjects (1.55±0.6 pg/mL, n=7; P<0.0005 and
P<0.0001, respectively) and in heart failure compared with
normal subjects (P<0.001).
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Discussion |
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This study has shown an elevation of the cytokines TNF-
and IL-6 in both myocardium and serum of donor hearts with
poor myocardial function compared with donor hearts with good
ventricular function. Elevated TNF- and IL-6 levels were
observed in all donor hearts, but the elevation was more marked in
those with poor ventricular function. Myocardial dysfunction has previously been shown in donor hearts and may have a variety of causes that include the effects of brain death, donor management, and myocardial preservation. Studies after brain death in experimental animals1 have shown decreased biventricular systolic function and contractility. Although several humoral and neurogenic factors have been implicated, the mechanisms underlying this remain unclear.
Our study suggests that the cytokines TNF- and IL-6 might
play a major role. This is supported by the fact that TNF- was
produced in the dysfunctional donor hearts in our study at levels
higher than that in advanced heart failure. Levels of TNF- were
higher in both the myocardium and serum in unused compared
with used donors and compared with advanced heart failure. Infusion of
TNF- into rats at similar levels to those found in patients with
end-stage heart failure results in depression of left
ventricular function, cardiac myocyte shortening, and left
ventricular dilation.9 In our study, TNF-
expression was demonstrated in cardiac myocytes in the dysfunctional
donor hearts. Cardiac myocytes have previously been shown to produce
substantial amounts of TNF-.12 It is therefore likely
that the TNF- produced by cardiac myocytes plays an important role
in causing donor heart dysfunction.
To the best of our knowledge, no other studies in humans have examined
the relation between cytokine expression and donor heart
malfunction. However, Takada and colleagues13 have shown
elevated TNF- and IL-6 mRNA in the myocardium and serum
of rats after explosive brain death along with other cytokines
produced by macrophages. They have also found cytokine
elevation in the kidney, brain, liver, and spleen.
The factors causing cytokine induction in donor hearts are
unclear. There was no relation between cytokine expression and
the cause of brain death in our study, with all types of brain injury
causing elevation of these cytokines. Brain death is known to
be associated with marked hemodynamic changes. We did
not monitor hemodynamic changes during the process of
brain death, but after brain death we observed no correlation between
TNF- and the donor central venous pressure, even though TNF-
production can be stimulated by pressure overload. Left
ventricular samples from unused donors and used donor
hearts were both transported in cardioplegia, but only the used donors
were transported as the whole organ, and the samples from patients with
end-stage heart failure were not transported at all. However, this is
unlikely to have affected cytokine measurement, particularly
because both TNF and IL-6 mRNA expression were independent of
ischemia time. Other potential causes of TNF- elevation in
the donor heart include drug therapy, neurohumoral factors, and
infection, although TNF expression was not related to infection in our
study.
TNF- acts on 2 cell surface receptors, TNFR1 (55 kDa) and TNFR2 (75
kDa), which are thought to mediate and regulate most of the effects of
TNF-, and both have been immunolocalized to cardiac
myocytes.14 TNF- produced in these donor hearts may
therefore act locally in either an autocrine or paracrine fashion by
binding to receptors situated on surrounding myocytes. The
extracellular domain fragments of both receptors are shed from cell
surfaces and can be detected as soluble forms (sTNFR1 and sTNFR2) in
blood and urine. Both soluble receptors have been shown to be elevated
in heart failure,15 which we also found in our study.
Although the exact biological role for these soluble TNF-binding
proteins is not known, it has been suggested that they may serve as
biological buffers that neutralize the highly cytotoxic activity of
TNF-, and experimentally it has been shown that soluble TNF
receptors are sufficient to both block and reverse the negative
inotropic effects of TNF-.16 It has also been
postulated that in the long term, soluble TNF receptors may stabilize
TNF- as a homotrimer and hence increase TNF bioactivity relative to
unstabilized TNF-, which dissociates into inactive monomers.
Interestingly, although raised levels of TNF- in the unused relative
to the used donors were detected in our study, the levels of the
receptors were no higher in the unused than the used donors, suggesting
that the rise in TNF- in the unused donors is not neutralized by a
similar rise in the TNF receptors.
Moreover, our group has previously demonstrated increased activity of
the inhibitory G protein, Gi, in
donor hearts with myocardial dysfunction.2 Treatment of
rat cardiomyocytes with TNF- causes a
concentration-dependent increase in
Gi,17 and this previously
documented rise in Gi may be a consequence of
TNF- expression, thus providing a pathway linking elevated TNF-
to impaired myocardial function. TNF- may act through several
different mechanisms. Binding of TNF- to TNFR1 results in the
production of sphingosine, which in turn decreases calcium
transients that may lead to dysfunctional excitation-contraction
coupling and to systolic and/or diastolic
dysfunction.18 TNF- can induce cardiac myocyte
apoptosis through a sphingosine-dependent
mechanism,19 and recent data from our group suggests that
activation of the apoptotic pathway occurs in dysfunctional
donor hearts.20 TNF- can also induce expression of
inducible nitric oxide synthase, resulting in the production of
nitric oxide, which itself can be negatively inotropic.3
Last, it has the potential to lead to heart failure through its effects
on the matrix metalloproteinases.21
IL-6 levels were higher in the myocardium of unused donors
compared with both used donors and patients with advanced heart failure
in our study. Elevated IL-6 has been demonstrated in the
peripheral circulation in heart failure,10 and
recently, one study showed IL-6 mRNA expression in the
myocardium11 of patients with heart failure.
Like TNF-, IL-6 can exert a negative inotropic
effect.22 Transgenic mice overexpressing the IL-6 gene and
its receptor, gp130, develop hypertrophy of the
ventricular myocardium and increase in heart
size,23 which may predispose to heart failure. TNF- can
induce IL-6 gene and protein expression in a variety of cell types, and
the rise in IL-6 seen in our study might be secondary to or independent
of TNF- release. Elevated IL-6 levels have been found previously to
correlate with elevated TNF- levels in heart failure,10
and it may be that a "cytokine cascade" is initiated. IL-6
levels also correlated with the amount of donor inotropic support in
our study. IL-6 levels have been shown to correlate with
norepinephrine levels in heart failure in previous
studies,10 and it is possible that the IL-6 elevation seen
in the donor hearts may be contributed to by the endogenous
norepinephrine known to be elevated after brain death or to
exogenous norepinephrine administered to these donors. IL-6
can be produced from leukocytes, endothelial cells, and
vascular smooth muscle cells in vitro and has recently been detected in
cardiac myocytes.24
Modulation of the expression of these cytokines might not only improve the functional results after transplantation but might potentially increase the use of organs from underutilized "marginal" donors and enlarge the donor pool.
Etanercept is a p75 TNF receptor fusion protein that binds to TNF-,
functionally inactivating it. When given to patients with NYHA class
III heart failure in a randomized double-blind trial, it increased
quality of life, 6-minute walk distance, and EF.25
Pentoxifylline is a xanthine derivative that suppresses or reduces the
production of TNF-. Administration of pentoxifylline to
patients with idiopathic dilated
cardiomyopathy26 resulted in improved
functional class, increased EF, and decreased TNF- levels.
Limitations of the Study
Although our results show an elevation of these cytokines
in dysfunctional donor hearts to levels sufficient to cause myocardial
dysfunction in other studies, a causal relation has not been
established. Further studies will be required in which these
cytokines are blocked and the functional results ascertained.
Our study was limited by the necessarily small amount of tissue
available from the donor hearts used for transplantation, which was
insufficient to allow protein studies for IL-6.
Conclusions
In conclusion, increased expression of the cytokines
TNF- and IL-6 was detected in the myocardium, with
similar changes in the serum of donor hearts with poor myocardial
function when compared with donor hearts with good
ventricular function. Pharmacological modulation of the
expression of these cytokines in organ donors might not only
improve the functional results after transplantation but might increase
the use of organs from "marginal" donors and possibly organs
previously considered untransplantable.
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Acknowledgments |
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We would like to thank the British Heart Foundation (BHF) for their support (project grant No. 96152). Emma J. Birks was supported by the BHF, Paul B.J. Burton by a MRC Clinical Training Fellowship, Paul J.R. Barton by a BHF Senior Research Fellowship, and Magdi H. Yacoub as a BHF Professor of Cardiothoracic Surgery. We would like to thank Mahrokh Nohadani for her invaluable technical help.
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