Circulation. 2005;112:I-46-I-50
doi: 10.1161/01.CIRCULATIONAHA.105.525873
(Circulation. 2005;112:I-46 – I-50.)
© 2005 American Heart Association, Inc.
Cardiac Transplantation and Surgery for Congestive Heart Failure |
Myocardial Insulin-Like Growth Factor-I Gene Expression During Recovery From Heart Failure After Combined Left Ventricular Assist Device and Clenbuterol Therapy
Paul J. R. Barton, PhD;
Leanne E. Felkin, BSc;
Emma J. Birks, MRCP, PhD;
Martin E. Cullen, PhD;
Nicholas R. Banner, FRCP;
Suzanne Grindle, BSc;
Jennifer L. Hall, PhD;
Leslie W. Miller, MD;
Magdi H. Yacoub, FRS
From the National Heart and Lung Institute, Imperial College London, Heart Science Centre, London (P.J.R.B., L.E.F., M.E.C., M.H.Y.), and Royal Brompton and Harefield NHS Trust, Harefield, Middlesex (E.J.B., N.R.B.), UK; and Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis (S.G., J.L.H., L.W.M.).
Correspondence to Paul J.R. Barton, Molecular Biology, Heart Science Centre, Harefield, Middlesex UB9 6JH, UK. E-mail p.barton{at}imperial.ac.uk
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Abstract
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Background— Patients who undergo mechanical support with
a left ventricular assist device (LVAD) exhibit reverse remodeling
and in some cases recover from heart failure. We have developed
a combination therapy using LVAD support combined with pharmacological
therapy to maximize reverse remodeling, followed by the ß
2 adrenergic agonist clenbuterol. We recently found that clenbuterol
induces insulin-like growth factor I (IGF-I) in cardiac myocytes
in vitro. The purpose of this study is to examine IGF-I expression
in recovery patients after combination therapy.
Methods and Results— Myocardial mRNA levels were determined by real-time quantitative polymerase chain reaction in 12 recovery patients (at LVAD implantation, explantation, and 1 year after explantation). IGF-I mRNA was elevated at the time of LVAD explantation relative to donors, with 2 groups distinguishable: Those with low IGF-I mRNA at implantation who showed significant increase during recovery and those with high IGF-I mRNA at implantation who remained high. Levels returned to normal by 1 year after explantation. Microarray analysis of implantation and explantation samples of recovery patients further revealed elevated IGF-II and IGF binding proteins IGFBP4 and IGFBP6. IGF-I levels correlated with stromal cell-derived factor mRNA measured both in LVAD patients and in a wider cohort of heart failure patients.
Conclusions— The data suggest involvement of elevated myocardial IGF-I mRNA in recovery. IGF-I may act to limit atrophy and apoptosis during reverse remodeling and to promote repair and regeneration in concert with stromal cell derived factor.
Key Words: polymerase chain reaction • myocardium • heart failure • growth substances • ventricles
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Introduction
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It is becoming increasingly recognized that mechanical support
of the failing human heart can result in recovery from heart
failure.
1 The overall rate of recovery remains low, however,
with an estimated frequency of approximately 5%.
2 In an attempt
to maximize the rate and durability of recovery, we have developed
a combination therapy whereby mechanical unloading using left
ventricular assist device (LVAD) support is combined with pharmacological
therapy aimed at maximizing reverse remodeling and then followed
by the use of the ß
2 adrenergic agonist clenbuterol
to stimulate physiological hypertrophy and improve cardiac function
(the Harefield Protocol).
3,4 To date, this has resulted in approximately
two thirds of patients who received the combination therapy
showing sufficient recovery to allow device removal without
the need for transplantation.
5 The mechanisms underlying the
process of recovery are unknown.
Clenbuterol can induce physiological hypertrophy in experimental models6 and has the unique ability to reverse pathological, functional, and molecular markers in the pressure-overloaded heart toward normality by normalizing systolic and diastolic function and SERCA2a mRNA levels and reducing collagen deposition.7,8 We recently found that clenbuterol induces insulin-like growth factor I (IGF-I) gene expression in cultured cardiac myocytes in vitro, 9 suggesting that local IGF-I may be an autocrine/paracrine mediator of the salutary effects of clenbuterol on the heart. IGF-I is known to exert many beneficial effects on the heart and can improve cardiac function in the failing heart in vivo,10 for example by attenuating the progression of heart failure in a model of dilated cardiomyopathy.11 Transgenic mice with cardiac overexpression of IGF-I initially develop physiological-type hypertrophy,12 and local IGF-I expression has been linked to stem cell recruitment in skeletal muscle13 and to the regenerative capacity of myocardium.11 In humans, IGF-I mRNA is elevated in compensated cardiac hypertrophy.14,15 In this study, we sought to test the hypothesis that myocardial IGF-I gene expression is elevated in patients undergoing combined LVAD and clenbuterol therapy and may therefore contribute to the recovery process. In addition, we investigated potential interactions between IGF-I and other gene families previously analyzed in these patients.
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Methods
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Patient Groups
Fifteen dilated cardiomyopathy patients who required LVAD implantation
because of deteriorating clinical status with evidence of secondary
organ dysfunction in the context of low cardiac output were
analyzed. Inclusion criteria were severe heart failure (New
York Heart Association functional class IV) due to dilated cardiomyopathy,
eligibility for heart transplantation (or expected eligibility
after LVAD), and deterioration despite optimal medical treatment
leading to the development acute heart failure (cardiac index
2 L · min
–1 · m
2) associated with high
filling pressure (pulmonary capillary wedge pressure
20 mm Hg)
despite inotrope support. Exclusion criteria were evidence of
irreversible multiorgan failure, incurable disease (eg, cancer
or metabolic disease), fixed elevated peripheral vascular resistance
in presence of severe right ventricular failure, cerebrovascular
disease, peripheral vascular disease with trophic lesions, or
previous prosthetic replacement of aortic or mitral valves.
For the patients studied here, mean duration of heart failure
symptoms before LVAD implantation was 43.9 months. All patients
were receiving inotropic support at the time of implantation.
During LVAD support, patients received a combination therapy
composed of mechanical support and administration of ß-blockers,
angiotensin-converting enzyme inhibitors, angiotensin II receptor
antagonists, and spironolactone, followed by administration
of clenbuterol to stimulate hypertrophy and improve cardiac
function.
3,4 Mean ejection fraction at time of implantation
was 10.3±5.2%. Mean duration of support was 387 days.
Twelve of the 15 patients showed sufficient myocardial recovery
to allow removal of the LVAD and were re-analyzed both at the
time of device removal and 1 year later. Immediately before
explantation, ejection fraction measured after the pump had
been turned off for 15 minutes was 65±6%. The study was
approved by the Royal Brompton and Harefield ethical review
committee and informed consent obtained from patients.
Myocardial Sample Analysis
Myocardial samples were obtained from the LV core taken at time of device implantation (n=15) and LV endomyocardial biopsies taken at time of device removal in the recovery patients (n=12). Where available, LV biopsy samples taken 1 year after device removal were also analyzed (n=8). RNA was extracted using methods adapted for maximal RNA recovery from endomyocardial biopsies16 and accurately quantified using RiboGreen (Invitrogen Ltd) to ensure equal loading of polymerase chain reactions (PCRs).16 A control group of RV biopsies from 10 used cardiac transplant donors with normal hemodynamic function was also analyzed, as well as 3 pairs of implant and explant samples from non-recovery LVAD patients after the combination therapy protocol. Reverse-transcription quantitative PCR was performed essentially as described17 using ABI PRISM 7700 and TaqMan chemistry. Expression levels were normalized using 18S rRNA with output data analyzed as described in figure legends. The IGF-I TaqMan assay used a minor groove binding probe that straddles an obligate splice site between exons 2 and 3 (Genbank accession # NM_000618, Probe: 5'-tgggcttgttgaaataa-3', forward primer: 5'-tccgactgctggagccata-3', reverse primer: 5'-gctggtggatgctcttcagtt-3'). The stromal cell derived factor-1 (SDF-1) assay was purchased as a pre-optimized kit from Applied Biosystems (Hs00171022_m1).
HG-U133A Affymetrix microarray analysis was performed essentially as described18,19 using RNA isolated from paired implant LV cores and single LV biopsies from each of 6 patients from the recovery group. Data were analyzed with Gene Expressionist (GeneData AG) using a hierarchical clustering algorithm to assess similarity. Normalized expression values were analyzed using Student’s paired t test.
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Results
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Initially we compared IGF-I mRNA levels during the time course
of recovery (
Figure 1). IGF-I mRNA levels were significantly
higher at the time of LVAD explantation compared with both donor
levels and levels 1 year after explantation. IGF-I mRNA levels
showed some elevation relative to those of donors at the time
of implantation. There was a further increase in IGF-I mRNA
at explantation, although this failed to reach significance
relative to the level at implantation. IGF-I mRNA levels were
variable at implantation, and 2 expression profiles could be
identified in the recovery group (
Figure 2). The groups were
those with low IGF-I mRNA levels at the time of implantation
(1.11±0.16 versus 1±0.26 [donors],
P=NS) who showed
significant increase during recovery (3.74±0.89-fold
increase relative to implant,
P<0.02) (
Figure 2A) and those
with high IGF-I at the time of implantation (4.25±0.5
versus 1±0.26 [donors],
P<0.001) who showed no significant
change with recovery (
Figure 2B).
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Figure 2. IGF-I mRNA levels in individual patients during recovery. Real-time PCR analysis of myocardial samples obtained from recovery patients at implantation, at explantation and 1 year after explant. mRNA levels were normalized to 18S rRNA and are shown on an arbitrary relative scale (calculated as 2– CT) for patients with (A) low or (B) high levels of IGF-I at implant.
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Levels of IGF-I mRNA at implantation were found to be inversely related to time from onset of symptoms (Figure 3a). Patients with high initial IGF-I levels had a significantly shorter time from onset of first symptoms to the time of LVAD support than patients with low IGF-I levels (14±9.8 months versus 70±22 months, P<0.05). Conversely, levels of IGF-I mRNA at implantation did not correlate with time to recovery (Figure 3B), nor was the degree of change in IGF-I mRNA expression during recovery related to the time of LVAD support (Figure 3C).
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Figure 3. IGF-I mRNA levels at time of implantation in relation to time. A, LVAD patients (n=15) were grouped according to high (>10) or low (<10) IGF-I as defined in Figure 2 and analyzed in relation to time from onset of symptoms to LVAD. B, Recovery patients were grouped as above and analyzed in relation to time from implantation to explantation. C, Change in IGF-I mRNA abundance in recovery patients relative to time on LVAD support.
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We used an unbiased microarray approach to further identify potential alterations in IGF-I signaling that take place during recovery in 6 paired implant and explant samples. This confirmed upregulation of IGF-I (2.38-fold increase at explantation, n=6, P<0.05) and further identified changes in IGF-II (1.88-fold increase, P<0.02) and IGF binding proteins IGFBP4 and IGFBP6 (2.13- and 2.10-fold increase respectively, P<0.02). There were no significant changes in the IGF receptor, the receptor regulatory subunits IRS-1 and IRS-2, or the downstream targets phosphoinositide 3-kinase or PKB/Akt.
To identify potential regulatory pathways involving IGF-I, we compared implantation and explantation IGF-I levels with expression levels of other genes previously determined by real-time PCR in the same patient samples.20 Positive correlation was found with matrix metalloproteinases MMP11 (r=0.49, P<0.001) and MMP14 (r=0.73, P<0.001), the tissue inhibitors of MMPs TIMP1 (r=0.42, P<0.01) and TIMP2 (r=0.43, P<0.01), and the stem cell factor stromal cell derived factor 1 (r=0.52, P<0.001) (Figure 4).
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Figure 4. IGF-I and SDF-1 mRNA levels correlate in a wide cohort of patients. Individual mRNA levels of IGF-I and SDF-1 were determined by real-time PCR in a large cohort of patients, including LVAD recovery patients and donor organs as described here, and end-stage heart failure as previously described.17 Data were normalized to 18S rRNA, plotted as raw CT values and analyzed by Spearman rank correlation (n=83, r=0.51, P<0.0001).
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Discussion
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This study is the first to examine IGF-I in LVAD patients in
the context of myocardial recovery after mechanical and pharmacological
therapy. IGF-I mRNA levels were elevated at the time of LVAD
explantation and returned to normal 1 year later (after device
removal and cessation of clenbuterol treatment). Alterations
in other parts of the IGF-I signaling pathway were also evident
at explantation, including elevated IGF-II and IGF binding proteins
IGFBP4 and IGFBP6. Close inspection of IGF-I mRNA levels at
the time of implantation identified 2 groups of patients defined
by IGF-I level at implant. Those with low IGF-I mRNA levels
had a longer time from onset of symptoms to the point of requiring
LVAD support, suggesting that IGF-I expression may be induced
after the onset of heart failure but that levels decline with
time. In these patients, the effect of the combination therapy
would appear to be related to maintaining high levels rather
than elevating IGF-I further. Patients with low IGF-I at implantation
showed marked increase between levels at implantation and explantation.
The mechanisms leading to elevated IGF-I expression in these
patients remain unknown. However, we recently demonstrated that
clenbuterol, an integral part of the Harefield bridge to recovery
protocol, can induce IGF-I gene expression in cultured cardiomyocytes
in vitro
9 and may therefore contribute to inducing IGF-I in
vivo. The contribution of mechanical unloading is currently
unknown but appears unlikely to contribute directly to IGF-I
expression, as previous studies using real-time PCR
21 and microarray
analysis
18 have failed to detect elevated IGF-I in LVAD patients
(those not taking clenbuterol and who do not recover) and mechanical
unloading of skeletal muscle does not induce IGF-I.
22
IGF-I is known to exert a number of potentially beneficial effects on the myocardium, including countering anti-apoptotic signaling, inducing adaptive hypertrophy, and reducing fibrosis.23 The data presented here are therefore consistent with the hypothesis that elevated IGF-I plays a positive role in the process of recovery. Our study differs from the only previous study on IGF-I in LVAD patients21 because we have focused specifically on sustained myocardial recovery as opposed to LVAD as a bridge to transplantation. This is an important distinction, as we have shown that structural remodeling and reversal of myocyte hypertrophy seen in many LVAD patients during mechanical unloading is not in itself an indicator of recovery.24 Our patient group is also distinguished by the use of clenbuterol. In the study by Razeghi et al,21 no change in IGF-I mRNA was observed during LVAD support and there was no evidence for IGF-I pathway activation (absence of Akt and IRS1 phosphorylation). This further suggests that elevated IGF-I may be specific to the recovery process. Our data derived from microarray analysis of paired implant and explant samples also point to recovery-specific changes in mRNA levels of the IGF binding proteins 4 and 6, as these were not evident in a previous array analysis of nonischemic patients undergoing LVAD support before transplantation.18
The role of elevated IGF-I in recovery is unknown, but IGF-I is known to exert a number of potentially positive effects on the myocardium. IGF-I can attenuate heart failure progression in a transgenic model of dilated cardiomyopathy, improving cardiac structure and function and reducing apoptosis.11 Local IGF-I expression results in skeletal muscle hypertrophy and sustained regenerative capacity in senescence.25 It also acts to limit skeletal muscle atrophy by inhibition of FOXO transcription factors and ubiquitin ligases Atrogin-1 and MuRF1.26,27 It is possible that the same mechanisms operate in cardiac muscle, thereby reducing the detrimental effects of excessive cardiac atrophy induced by mechanical unloading. Because of the limited availability of material (generally a single biopsy obtained at explantation and another at 1 year after explantation) we were unable to examine pathway activation in detail in these patients, and previous studies in LVAD patients undergoing bridge to transplant have provided conflicting results of Akt activation.28,29 Nonetheless, we identified alterations in gene expression of other components of the IGF-I signaling pathway during recovery, including elevation of binding proteins IGFBP4 and 6, which could be expected to impact IGF-I activity.
To identify potential regulatory pathways involving IGF-I in recovery, we correlated IGF-I expression levels with those of other genes previously analyzed in the same samples, including the natriuretic factors (ANP and BNP), cytokines (interleukin-6, interleukin-1ß and tumor-necrosis factor-
), MMPs 1 to 14 and TIMPs 1 to 4 and selected myocardial transcription factors (GATA4, HAND1 and HAND2) (data not shown). Positive correlation was observed between IGF-I and MMPs 11 and 14 and with TIMPs 1 and 2, suggesting a potential link between IGF-I expression and alterations in extracellular matrix metabolism. We also identified a positive correlation between IGF-I and the stem cell recruitment factor SDF-1 (see Figure 4), which has previously been shown to play a role in the myocardial response to damage.30 Recent studies have shown that local IGF-I production may itself act as a stem cell recruitment factor in skeletal muscle,13 and cardiac over-expression of IGF-I in heart has been shown to elevate markers of cell division and stem cell recruitment.11,23 It is therefore possible that elevated IGF-I acts as part of a survival and regeneration program in recovery. Our data show that SDF-1 and IGF-I mRNA levels correlate both in LVAD patients and in a wider cohort, suggesting this correlation may indeed be a general feature of heart failure.
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Conclusion
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The data presented here demonstrate that elevated IGF-I mRNA
at explantation is a feature of LVAD patients who receive the
Harefield protocol and who recover from heart failure. The mechanisms
leading to elevated IGF-I expression remain unknown but may
relate to the use of clenbuterol.
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Acknowledgments
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The authors are grateful to the British Heart Foundation, the
Magdi Yacoub Institute, The Royal Brompton and Harefield Charitable
Trustees, The Lillehei Heart Institute University of Minnesota,
and Thoratec Corporation for supporting this work.
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References
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|---|
- Frazier OH, Benedict CR, Radovancevic B, Bick RJ, Capek P, Springer WE, Macris MP, Delgado R, Buja LM. Improved left ventricular function after chronic left ventricular unloading. Ann Thorac Surg. 1996; 62: 675–681.[Abstract/Free Full Text]
- Mancini DM, Beniaminovitz A, Levin H, Catanese K, Flannery M, DiTullio M, Savin S, Cordisco ME, Rose E, Oz M. Low incidence of myocardial recovery after left ventricular assist device implantation in patients with chronic heart failure. Circulation. 1998; 98: 2383–2389.[Abstract/Free Full Text]
- Yacoub MH. A novel strategy to maximise the efficacy of left ventricular assist devices as a bridge to recovery. Eur Heart J. 2001; 22: 534–540.[Free Full Text]
- Yacoub MH, Birks EJ, Tansley P, Bowles CT. Bridge to recovery: the Harefield approach. J Congest Heart Fail Circul Supp. 2001; 2: 27–30.
- Yacoub M, Tansley P, Birks E, Hipkin M, Hardy J, Bowles C, Banner N, Khaghani A. Interim results of left ventricular assist device combination therapy for inducing clinical and haemodynamic recovery of end stage dilated cardiomyopathy. Circulation. 2002; 106: S2995–I.
- Petrou M, Wynne DG, Boheler KR, Yacoub MH. Clenbuterol induces hypertrophy of the latissimus dorsi muscle and heart in the rat with molecular and phenotypic changes. Circulation. 1995; 92: 483–489.[Abstract/Free Full Text]
- Wong K, Boheler KR, Petrou M, Yacoub MH. Pharmacological modulation of pressure-overload cardiac hypertrophy: changes in ventricular function, extracellular matrix and gene expression. Circulation. 1997; 96: 2239–2246.[Abstract/Free Full Text]
- Hon JK, Steendijk P, Petrou M, Wong K, Yacoub MH. Influence of clenbuterol treatment during six weeks of chronic right ventricular pressure overload as studied with pressure-volume analysis. J Thorac Cardiovasc Surg. 2001; 122: 767–774.[Abstract/Free Full Text]
- Barton PJR, Bhavsar PK, Felkin LE, Sugden PH, Yacoub MH. Morphological and molecular effects of clenbuterol on cardiac myocytes: role of IGF-1. J Heart Lung Transplant. 2004; 23: S53–S54.
- Duerr RL, Huang S, Miraliakbar HR, Clark R, Chien KR, Ross J Jr. Insulin-like growth factor-1 enhances ventricular hypertrophy and function during the onset of experimental cardiac failure. J Clin Invest. 1995; 95: 619–627.
- Welch S, Plank D, Witt S, Glascock B, Schaefer E, Chimenti S, Andreoli AM, Limana F, Leri A, Kajstura J, Anversa P, Sussman MA. Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice. Circ Res. 2002; 90: 641–648.[Abstract/Free Full Text]
- Delaughter MC, Taffet GE, Fiorotto ML, Entman ML, Schwartz RJ. Local insulin-like growth factor I expression induces physiologic, then pathologic, cardiac hypertrophy in transgenic mice. FASEB J. 1999; 13: 1923–1929.[Abstract/Free Full Text]
- Musaro A, Giacinti C, Borsellino G, Dobrowolny G, Pelosi L, Cairns L, Ottolenghi S, Cossu G, Bernardi G, Battistini L, Molinaro M, Rosenthal N. Stem cell-mediated muscle regeneration is enhanced by local isoform of insulin-like growth factor 1. Proc Natl Acad Sci U S A. 2004; 101: 1206–1210.[Abstract/Free Full Text]
- Neri Serneri GG, Modesti PA, Boddi M, Cecioni I, Paniccia R, Coppo M, Galanti G, Simonetti I, Vanni S, Papa L, Bandinelli B, Migliorini A, Modesti A, Maccherini M, Sani G, Toscano M. Cardiac growth factors in human hypertrophy: relations with myocardial contractility and wall stress. Circ Res. 1999; 85: 57–67.[Abstract/Free Full Text]
- Neri Serneri GG, Boddi M, Modesti PA, Cecioni I, Coppo M, Padeletti L, Michelucci A, Colella A, Galanti G. Increased cardiac sympathetic activity and insulin-like growth factor-I formation are associated with physiological hypertrophy in athletes. Circ Res. 2001; 89: 977–982.[Abstract/Free Full Text]
- Felkin LE, Taegtmeyer AB, Barton PJR. Real-time quantitative PCR in cardiac transplant research.In: Hornick P, Rose ML, eds. Transplantation Immunology. Humana Press; Totowa, NJ 2005.
- Barton PJR, Birks EJ, Felkin LE, Cullen ME, Koban MU, Yacoub MH. Increased expression of extracellular matrix regulators TIMP1 and MMP1 in deteriorating heart failure. J Heart Lung Transplant. 2003; 22: 738–744.[CrossRef][Medline]
[Order article via Infotrieve]
- Hall JL, Grindle S, Han X, Fermin D, Park S, Chen Y, Bache RJ, Mariash A, Guan Z, Ormaza S, Thompson J, Graziano J, Sam Lazaro SE, Pan S, Simari RD, Miller LW. Genomic profiling of the human heart before and after mechanical support with a ventricular assist device reveals alterations in vascular signaling networks. Physiol Genomics. 2004; 17: 283–291.[Abstract/Free Full Text]
- Huebert RC, Li Q, Adhikari N, Charles NJ, Han X, Ezzat MK, Grindle S, Park S, Ormaza S, Fermin D, Miller LW, Hall JL. Identification and regulation of Sprouty1, a negative inhibitor of the ERK cascade, in the human heart. Physiol Genomics. 2004; 18: 284–289.[Abstract/Free Full Text]
- Felkin LE, Birks EJ, Hall JL, Miller LW, Barton PJ. Altered gene expression of tissue inhibitors of metalloproteinases in clinical recovery of heart failure with combined left ventricular assist device and clenbuterol therapy. Circulation. 2004; 110: III–632. Abstract.
- Razeghi P, Bruckner BA, Sharma S, Youker KA, Frazier OH, Taegtmeyer H. Mechanical unloading of the failing human heart fails to activate the protein kinase B/Akt/glycogen synthase kinase-3beta survival pathway. Cardiology. 2003; 100: 17–22.[CrossRef][Medline]
[Order article via Infotrieve]
- Awede B, Thissen J, Gailly P, Lebacq J. Regulation of IGF-I, IGFBP-4 and IGFBP-5 gene expression by loading in mouse skeletal muscle. FEBS Lett. 1999; 461: 263–267.[CrossRef][Medline]
[Order article via Infotrieve]
- Torella D, Rota M, Nurzynska D, Musso E, Monsen A, Shiraishi I, Zias E, Walsh K, Rosenzweig A, Sussman MA, Urbanek K, Nadal-Ginard B, Kajstura J, Anversa P, Leri A. Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpression. Circ Res. 2004; 94: 514–524.[Abstract/Free Full Text]
- Terracciano CM, Hardy J, Birks EJ, Khaghani A, Banner NR, Yacoub MH. Clinical recovery from end-stage heart failure using left-ventricular assist device and pharmacological therapy correlates with increased sarcoplasmic reticulum calcium content but not with regression of cellular hypertrophy. Circulation. 2004; 109: 2263–2265.[Abstract/Free Full Text]
- Musaro A, McCullagh K, Paul A, Houghton L, Dobrowolny G, Molinaro M, Barton ER, Sweeney HL, Rosenthal N. Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet. 2001; 27: 195–200.[CrossRef][Medline]
[Order article via Infotrieve]
- Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD, Glass DJ. The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell. 2004; 14: 395–403.[CrossRef][Medline]
[Order article via Infotrieve]
- Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 2004; 117: 399–412.[CrossRef][Medline]
[Order article via Infotrieve]
- Razeghi P, Taegtmeyer H. Activity of the Akt/GSK-3beta pathway in the failing human heart before and after left ventricular assist device support. Cardiovasc Res. 2004; 61: 196–197.[Free Full Text]
- Baba HA, Stypmann J, Grabellus F, Kirchhof P, Sokoll A, Schafers M, Takeda A, Wilhelm MJ, Scheld HH, Takeda N, Breithardt G, Levkau B. Dynamic regulation of MEK/Erks and Akt/GSK-3beta in human end-stage heart failure after left ventricular mechanical support: myocardial mechanotransduction-sensitivity as a possible molecular mechanism. Cardiovasc Res. 2003; 59: 390–399.[Abstract/Free Full Text]
- Askari AT, Unzek S, Popovic ZB, Goldman CK, Forudi F, Kiedrowski M, Rovner A, Ellis SG, Thomas JD, DiCorleto PE, Topol EJ, Penn MS. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet. 2003; 362: 697–703.[CrossRef][Medline]
[Order article via Infotrieve]
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Abstract
Introduction