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European Heart Journal Advance Access originally published online on November 28, 2006
European Heart Journal 2007 28(5):613-627; doi:10.1093/eurheartj/ehl365
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Molecular signature of recovery following combination left ventricular assist device (LVAD) support and pharmacologic therapy

Jennifer L. Hall1,*, Emma J. Birks2,3, Suzanne Grindle1, Martin E. Cullen2, Paul J. Barton2, James E. Rider1, Sangjin Lee1, Subash Harwalker1, Ami Mariash1, Neeta Adhikari1, Nathan J. Charles1, Leanne E. Felkin2, Sean Polster1, Robert S. George2, Leslie W. Miller1 and Magdi H. Yacoub2,4

1 Lillehei Heart Institute, Division of Cardiology, Department of Medicine, University of Minnesota, Mayo Mail Code 508, 420 Delaware Street SE, Minneapolis, MN 55455, USA
2 Heart Science Centre, National Heart and Lung Institute, Imperial College, Harefield, Middlesex, UK
3 Transplant Unit, Royal Brompton and Harefield NHS Trust, Harefield, Middlesex, UK
4 University of Florence, Florence, Italy

Received 9 July 2006; revised 29 September 2006; accepted 20 October 2006; online publish-ahead-of-print 28 November 2006.

* Corresponding author. Tel: +1 612 626 4566; fax: +1 612 626 4411.E-mail address: jlhall{at}umn.edu

See page 522 for the editorial comment on this article (doi:10.1093/eurheartj/ehl555)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Aims A novel combination therapy consisting of a left ventricular assist device (LVAD) combined with pharmacologic therapy including the selective ß2-agonist, clenbuterol, has shown promise in restoring ventricular function in patients with heart failure. The aim of this study was to identify common genes and signalling pathways whose expression was associated with reversal of heart failure and restoration of ventricular function.

Methods and results Microarray analysis was performed on six paired human heart samples harvested at the time of LVAD implant and at the time of LVAD explant for recovery of ventricular function (post). Follow-up data shows that the improvements in ventricular function have been maintained for an average of 3.8 years post-explant. Analysis of the gene expression data revealed: (i) a significant association of integrin pathway signalling with recovery and (ii) the identification of several novel targets including, EPAC2, in the well-described cAMP pathway whose expression was down-regulated with recovery, and was associated with improvements in cardiac contractility, metabolism, and function.

Conclusion This data set represents the first description of signalling pathways associated with the functional recovery of end-stage human heart failure and the identification of new targets in the human heart that are modified by this combination therapy.

Key Words: Heart failure • Left ventricular assist device • EPAC2 • Genomics • Gene expression


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
Heart failure is a syndrome of increasing prevalence resulting in high mortality and enormous economic impact.1 Progression to heart failure involves progressive remodelling of the ventricle characterized by structural changes and changes in expression of a multitude of genes.

The current limitations of animal models to replicate a complex disease such as heart failure are becoming more apparent. The use of human tissue to define critical gene and signalling pathways governing cardiovascular remodelling is thus of utmost importance. The ability to analyse paired human heart samples from patients in end-stage heart failure pre- and post-left ventricular assist device (LVAD) has been useful in identifying genes that are involved in reverse remodelling of the dilated heart.2–11 However, although partial recovery of myocyte function has been reported with the LVAD,12–14 only 5% of these patients achieve sufficient recovery of function to allow explant of the device.15 A novel combination therapy consisting of unloading of the ventricle with an LVAD followed by an initiation of five drugs designed to induce myocardial reverse remodelling plus a selective ß2-agonist, clenbuterol, has shown promise in near total recovery and maintaining function in patients with non-ischaemic refractory heart failure.16,17 To our knowledge, this is the first study to identify changes in gene expression, including expression of components of signalling pathways that occur in the functional recovery of end-stage human heart failure.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
Patients
A total of 15 patients were prospectively recruited into a study in which they received combination therapy (further details of recruitment are provided in Birks et al., NEJM).18 Of these 15 patients, 11 recovered sufficiently to be explanted. The array analysis was performed on six patients with non-ischaemic cardiomyopathy in which sufficient tissue was harvested. All six received the combination therapy that initially included placement of an LVAD. Early post-operatively, all patients received ß-blockers, an ACE-inhibitor, an angiotensin II blocker, digoxin, and an aldosterone receptor-blocker at 2–3 months, which was followed by the addition of the ß2-agonist clenbuterol. Mean ejection fraction (EF) at implantation was 8.5 ± 3.5% (Table 1). Immediately prior to explantation, mean EF, with the pump turned off for 15 min, was 65.8%. Myocardial left ventricular samples were collected during both LVAD implantation and explantation. All tissues were immediately frozen in liquid nitrogen and stored at –80°C. The Royal Brompton and Harefield NHS Trust Ethics Committee and the University of Minnesota Institutional Review Board approved the study and informed consent was obtained from all participating patients prior to tissue collection.


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  		Table 1 Patient data from six patients achieving recovery from combination therapy. Table includes age at the time of LVAD implant, gender, EF pre-implant and pre-explant, inotropes, and time on LVAD (days). DP, dopamine; DB, dobutamine; NA, noradrenaline; ML, milrinone

 
Sample preparation
Tissue collection, RNA isolation, cDNA synthesis, in vitro transcription-synthesis of biotin-labelled cRNA, target hybridization, and probe array was performed as previously described.5

Real-time quantitative PCR
Real-time quantitative PCR (RTQPCR) was used in both collaborating laboratories as previously described at the University of Minnesota with the Roche Light Cycler,5 and Imperial College London with Taqman (Applied Biosystems).3 Primers included:

integrin {alpha}5 Forward 5'-AGCCTCAGAAGGAGGAGGAC-3'

integrin {alpha}5 Reverse 5'-GGTTAATGGGGTGATTGGTG-3'

{alpha}1 actinin Forward 5'-TCATCTCAGGTGAACGCTTG-3'

{alpha}1 actinin Reverse 5'-AGATGTCCTGGATGGCAAAG-3'

GAPDH Forward 5'-ACCACAGTCCATGCCATCAC-3'

GAPDH Reverse 5'-TCCACCACCCTGTTGCTGTA-3'.

Transcripts analysed at Imperial College London using Applied Biosystems' Assays on Demand included Sfrp1 (Hs00610060_m1), AGAT (Hs00155208_m1), and Rap guanine nucleotide exchange factor (RAPGEF4/EPAC2) (Hs00199754_m1).

Data analysis
To define the signalling pathways highly enriched with genes whose expression was significant in the recovering hearts, we utilized Ingenuity Pathways Analysis (www.ingenuity.com). Ingenuity is one of several commercially available programs that dynamically computes a large ‘global’ molecular network based on hundreds of thousands of curated direct and indirect physical and functional interactions between orthologous mammalian genes from the published, peer-reviewed content in Ingenuity's Knowledge Base. This allowed us to test whether relationships existed between the list of statistically significant genes generated from analysing paired pre- and post-LVAD samples from a cohort of recovered patients. The Ingenuity Pathways Knowledge Base currently contains well over 1 000 000 expert modeled findings plus several hundreds of thousands of additional interactions acquired by automated extraction processes. Significance/P-values in Ingenuity Pathways Analysis are calculated based on a hypergeometric distribution calculated via the computationally efficient Fisher's Exact Test for 2 x 2 contingency tables. More precisely, it is the right-tailed Fisher's Exact test given that only over-represented functional pathway annotations are listed. Two gene lists were imported into Ingenuity for the analysis. The first was a paired T-test of pre- vs. post-LVAD samples with a P-value < 0.05 with no cutoff for fold change (515 genes). The second list was generated from a paired T-test with a more stringent set of parameters—P-value < 0.01 (263 genes) (Table 2). The final analysis included the intersection of genes that were significant at P < 0.01 with both paired and unpaired T-tests to generate the list of 98 genes in Table 3. This type of analysis enriches genes that are consistently expressed in all pre- and post-LVAD samples and genes that are reproducible either up- or down-regulated following LVAD explant.


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  		Table 2 List of 263 genes significantly changed with a paired T-test following recovery in six patients receiving combination therapy [P < 0.01, n = six paired samples (pre-LVAD implant, post-LVAD, post-explant)]

 

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  		Table 3 List of 98 genes that were significantly changed in recovery patients following combination therapy (P < 0.01, n = six paired samples (pre-LVAD (implant), post-LVAD (explant))

 

   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
Table 1 outlines the patient data. These six patients are now a mean of 3.8 (range 2–4.7) years post-explantation and have successfully maintained the initial improvements in cardiac function seen with this combination therapy. The objective of this study was to begin to define key genes and signalling pathways that were associated with recovery from human heart failure. We outline a series of three different analyses that (i) identify pathways significantly enriched with genes whose expression is statistically different between heart failure and recovery, (ii) reveal novel genes in a well-described pathway known to play an important role in cardiovascular function (cAMP signalling), and (iii) determine interaction/cross talk among pathways of interest by focusing on new gene targets.

A total of 263 genes were identified as significantly up- or down-regulated in the recovered hearts (paired T-test, P < 0.01) (Table 2). The intersection of genes that were statistically significant using both as paired and unpaired T-test were also identified (98 genes, P < 0.01, Table 3). This intersection approach produces a list of genes with relatively low variability at baseline and which are consistently modulated in response to the recovery therapy. This approach allows us to identify and focus on particular genes of interest for further analysis—akin to the modus operandi of many classically trained biologists.

An alternative approach is to examine the profile of genes together as a whole with the goal of identifying networks that are altered in the process of recovery from heart failure. To do this we used Ingenuity, one of several commercially available programs that construct connectivity networks of genes curated from the literature. Put simply, one imports gene lists into the Ingenuity database and the program overlays these genes into several described networks to identify the best overall fit. In order to optimize the use of all genes in the signalling networks, we utilized Ingenuity's Pathways Analysis program, which employed a right-tailed Fisher's exact test. One of the most significant pathways identified was the integrin pathway with a P-value of 0.006. Genes in the integrin signalling pathway included integrin {alpha}5 (ITGA5, up-regulated 2.0-fold), {alpha}1 actinin (ACTN1, up-regulated 2.4-fold), actin-related protein 2/3 complex (ARP2/3, up-regulated 1.6-fold), GTP-binding protein (Cdc42, up-regulated 1.3-fold), Rhodopsin (RHO, down-regulated 1.3-fold), Vinculin (VCL, down-regulated 1.4-fold), protein phosphatase 1 regulatory subunit (MLCP/PP1R12B, up-regulated 1.5-fold), and ß actin (ACTB).19 We have recently published this work in more detail.19 RTQPCR was used to confirm a subset of these selected genes that fall in different signalling pathways including alpha 1 actinin (ACTN1) (up-regulated 2.3-fold by RTQPCR, 2.0-fold with array)19 and alpha-5 integrin (ITGA5) (up-regulated 1.8-fold by RTQPCR, 2.5-fold with array)19.

Next, we utilized Ingenuity to identify a novel gene in a well-described signalling pathway. The cAMP-mediated signalling pathway, a pathway known to play a key role in heart failure was assigned a less significant P-value of 0.5 (compared with 0.006 for the Integrin Pathway). The genes in the cAMP-mediated signalling pathway included Rap guanine nucleotide exchange factor 4 (RAPGEF4 (EPAC2), down-regulated 2.2-fold), protein kinase, cAMP-dependent, regulatory, type I alpha (tissue-specific extinguisher 1) (PKAr, down-regulated 1.5-fold), phosphodiesterase 1A (PDE1A, down-regulated 1.5-fold), phosphodiesterase 3B (PDE3B, down-regulated 1.5-fold), and calcineurin A (PPP3CA/PP2B, (up-regulated 1.4-fold) (Figure 1). Despite the lack of significance assigned to this pathway, it permitted us to identify an association between a new member of this well known signalling pathway, EPAC2, and recovery from heart failure. The down-regulation of the recently defined EPAC2 gene in the hearts of all six of the recovered patients and three new additional subjects is shown in Figure 2A. The down-regulation of EPAC2 did not occur in a set of non-recovered non-ischaemic patients and was thus unique to the recovered cohort as seen in Figure 2B.


Figure 1
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  		Figure 1 Identification of genes in the well known cAMP-mediated signalling pathway whose expression was altered in association with recovery. Shaded symbols represent genes whose expression was significantly altered in explanted vs. implanted samples. This pathway analysis approach highlighted a previously unacknowledged role for EPAC2 in this process of recovery.

 

Figure 2
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  		Figure 2 RTQPCR reconfirmed the down-regulation in EPAC2 in the explanted heart samples compared with the paired implant samples in all six recovered patients from the array analysis and extended these findings to an additional five recovered patients, n = 11, P < 0.01. EPAC2 values were unchanged in a set of non-recovered paired human heart samples (n = 5, P-value, not significant).

 
The final goal was to highlight previously unrecognized interactions between the genes that were significantly regulated in recovered patients. The goal of this type of analysis is to identify novel signal transduction pathways associated with recovery of end-stage heart failure. Genes found to be statistically significant were grouped onto networks based upon Ingenuity Pathways Knowledge Base of interacting genes. Two networks were identified (Figure 3 and 4). The first network is shown in Figure 3. Of particular interest in this pathway was the link between EPAC2 and insulin. This interaction is supported by a number of recent studies in pancreatic islet cells and may play an important role in metabolism as well as its better known role in calcium signalling. Secondly, a number of the genes included in the integrin signalling in Figure 1 are shown to interact with TNF (alpha-5 integrin) and c-myc (alpha 1 actinin) in Figure 3. The second network identified is shown in Figure 4 and includes arginine:glycine amidinotransferase (AGAT, GATM) (down-regulated 2.9-fold by array).20 RTQPCR reconfirmed this finding, and identified a 3.4-fold down-regulation. Interestingly, AGAT, which is an enzyme that regulates expression of creatine, appears to interact with MAPKAP2 and IL-4.


Figure 3
Figure 3
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  		Figure 3 Identification of the potential interactions between genes associated with recovery. Of note is the link between RAPGEF4 (EPAC2) and insulin, and the connection between integrin signalling genes including alpha-5 integrin and alpha-1 actinin with TNF and c-myc, respectively. The fold change in the connected table represents direction in the explanted sample.

 

Figure 4
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  		Figure 4 Identification of the potential interactions between genes associated with recovery. Note the association of GATM with IL-4. Fold change represents direction in explanted sample.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
To our knowledge, this is the first full report of the signature of genes associated with the recovery of refractory human heart failure. In this analysis, we highlight: (i) a significant association between recovery and integrin signalling pathways and (ii) a significant down-regulation of the novel gene EPAC2, a guanine nucleotide exchange factor that binds to cAMP and is associated with signalling pathways that improve ß-adrenergic responsiveness and myocyte contractility. The identification of these networks came about through an integrated approach of both focusing in on single genes and utilizing a systems approach to analyse the data. Although the classical single gene approach has been successful in identifying dysregulated molecular and cellular signalling associated with heart failure, we now have the opportunity to exploit new approaches to further understand the mechanisms of cardiovascular disease and recovery. These new approaches include system-wide approaches including those used in this study in which we are able to organize genes into pathways associated with recovery from end-stage heart failure.

LV unloading in end-stage heart failure patients with LVAD support has been shown to improve myocardial structure and function, including improving ß-adrenergic responsiveness and myocyte contractility.21,22 Several working groups, including our own, have defined changes in gene expression that occur with LVAD support that appear to be important in improving ß-adrenergic responsiveness and calcium handling including partial restoration of ß-receptor density, and altered regulation of the genes in G-protein-regulated signalling and calcium handling.4,5,7,23,24 However, despite near normalization of these measurements, these patients rarely achieve sufficient recovery of ventricular previously function to allow explantation of the device. Given the defined species heterogeneity with respect to ß-adrenergic receptor density and signalling,25 analysis of human tissue provides a significant opportunity to advance our understanding of the regulation and role of adrenergic signalling in human recovery.

EPAC2 has been shown to tether cAMP to MAPK, calcium-mediated signalling through NFAT, and metabolic signalling pathways.26,27 We reconfirmed the decrease in EPAC2 by RTQPCR (Figure 2). Recent work published by our group28 identified a significant increase in flux through the Kreb's cycle of adult rat cardiac myocytes treated with clenbuterol. In addition, Soppa et al.28 identified a significant improvement in calcium handling in myocytes treated with clenbuterol. It is possible that these affects were in part mediated through EPAC2. The down-regulation in EPAC2 appears to be unique to recovery as we did not find any significant changes in EPAC2 in previously analysed non-recovered samples.

Pathway analysis also identified an integrin pathway that was enriched with genes significantly altered by recovery. This is in agreement with our previous work, demonstrating changes in integrin pathway components (integrins {alpha}5, {alpha}7, ß1, ß6, ß7, vinculin, {alpha}2-actinin, ß actin) at both mRNA and protein levels.19 There is a growing body of evidence that integrins are bidirectional signalling molecules and play a role in mechanotransduction by mediating mechanical (stretch) signals from the extracellular matrix, via protein kinase cascades that provoke changes in gene expression, including those involved in the hypertrophic response.29–33 These data suggest that the integrin pathway may play a key role at the molecular and cellular level in processes of reverse remodelling and subsequent functional recovery occurring in these patients. Whether patients with ischaemic aetiology would have similar changes in gene expression with this therapy is unclear.

In addition to the finding that the process of recovery was associated with cAMP and integrin signalling, several new targets were identified. Arginine:glycine amidinotransferase (AGAT), a rate-limiting enzyme in the creatine synthesis pathway, was significantly down-regulated following unloading in the recovered hearts, returning to normal levels in direct contrast to the up-regulation of AGAT in patients with heart failure compared with donor hearts.20 These changes in AGAT mRNA levels suggest a response to heart failure that involves elevated local creatine synthesis. The mechanisms leading to induced AGAT expression are unknown but may be a response to the depletion of the local creatine pool, which we and others have shown to be a feature of heart failure.

We recognize that a sample size of six patients is a limitation of this study. However, the association between genes that are significantly altered in the process of myocardial recovery with the prospective follow-up over a minimal course of 2 years showing ventricular function in all six patients remains normal (mean EF 66%) provides an important starting point. The inclusion of both genders is also a limitation that likely decreases the sensitivity of the analysis. Histological analysis of the pre-LVAD heart samples revealed no sign of acute myocarditis. Furthermore, analysis of the pre-LVAD samples from this recovery cohort with 19 pre-LVAD non-recovered samples in our expression library revealed less than 2% change in the number of statistically significant genes (73 genes) (P < 0.01, two-fold change), suggesting our recovered patients are comparable to non-recovered patients prior to LVAD insertion. We are unable to state with certainty that these gene differences are not relevant to the ability to recover. Four of the 73 genes identified as significantly different between the pre-recovered and the pre-non-recovered were interferon, gamma-inducible protein 16, mannose receptor, C type 1, serine/arginine repetitive matrix 2, and S100 calcium binding protein A10. Despite the relatively small sample size, the paired design of the study helps to alleviate the confounding factor of human heterogeneity. Although the analysis tools used to identify networks and pathways provide an advantageous resource for determining pathways that may be associated with recovery, these programs are currently limited by the amount of information within the database.

In conclusion, this study provides a first molecular signature of clinical recovery in patients with heart failure. This study combines the use of genomics in a unique patient population that represents recovery from end-stage heart failure with follow-up clinical data demonstrating maintained improvement in heart function. Novel associations included a robust regulation of integrin signalling pathways; and a point-specific regulation of a novel gene, EPAC2, in the cAMP signalling pathway that is associated with historical improvements in contractility, ß-adrenergic responsiveness, and metabolic signalling. In many ways it is surprising that common pathways and genes are identified that associate with recovery given that the genetic and environmental cues that predisposed these patients to a complex disease such as heart failure are likely to be dissimilar. The use of genome-wide association studies to identify common variants in genes associated with early onset or rapid progression of heart failure in multiple large populations will provide important clues and additional insights in mining microarray datasets such as this. For example, it is foreseeable that we will have the capacity to determine genes whose expression is driven in large part through environmental influences vs. those whose expression is driven in large part by heritable variants in the genome. Incorporating the use of more large-scale platforms and bioinformatics analyses in the study of human heart failure will hopefully advance our understanding of human disease and potentially lead to the identification of new drug therapies to slow or reverse the disease.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
The authors wish to thank the staff at the University of Minnesota Affymetrix Core Facility, the staff of the Supercomputing Institute for Digital Simulation and Advanced Computation at the University of Minnesota, The Royal Brompton and Harefield Charitable Trustees, Thoratec Corporation, and the British Heart Foundation for their generous support.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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