European Heart Journal Advance Access published online on February 21, 2007
European Heart Journal, doi:10.1093/eurheartj/ehl555
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Gene expression profile of the recovering human heart
1 Division of Cardiology, University of Colorado Health Sciences Center, Denver, CO 80262, USA
2 Division of Cardiology, University of Rochester Medical Center, Rochester, NY 14642, USA
3 Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
* Corresponding author. Tel: +1 585 273 1094; fax: +1 585 276 1914. E-mail address: burns_blaxall{at}urmc.rochester.edu
Heart failure is a disease of increasing prevalence and poor prognosis. Current data indicate that 5-year survival following the diagnosis of heart failure is 50%, and patients with end-stage disease face a 1-year survival rate of 50%. Recent predictions suggest that heart failure will become the leading cause of all disability by 2020. For patients with refractory end-stage heart failure, there are few options for effective treatment. Although cardiac transplantation provides the best therapeutic outcome for end-stage HF, substantial limitations of this surgical intervention include an extremely limited supply of acceptable donor hearts, having reached a plateau of less than 3000 per year worldwide.
Left ventricular assist device (LVAD) support of end-stage heart failure patients was originally approved as a bridge to cardiac transplant, and recent reports suggest improved outcomes in transplant recipients supported by LVAD in comparison with those treated with chronic inotropes.1 Improved morbidity and mortality were found in the REMATCH trial of long-term LVAD support compared with optimized medical management in severe HF patients ineligible for transplant, leading to the approval of LVAD as destination therapy.
Unloading the left ventricle in end-stage heart failure patients with LVAD support can lead to partial normalization of myocardial structure and function, termed reverse remodelling. Reverse remodelling has been associated with changes in gene expression following LVAD support2–6 or pharmacological therapy.7 In select patients, LVAD support in conjunction with pharmacological therapy may result in sufficient reverse remodelling to allow explant of the device. LVAD-associated reverse remodelling provides the unique opportunity to obtain myocardial tissue in humans in end-stage heart failure at the time of LVAD implant and subsequent explant upon myocardial recovery or transplantation. This allows for the serial analysis of gene expression profiles in the same patient that may provide important insights into both the progression and regression of heart failure.
Hall et al.8 report global analysis of gene expression changes in heart failure patients they have recently described,9 who were supported with LVAD, the ß2-adrenergic receptor (ß2-AR) agonist clenbuterol, and additional pharmacological management. Using a pathway analysis strategy, the authors identified several changes in the integrin pathway associated with recovery, supporting their previously reported single gene findings in these same patients.10,11 Less compelling alterations were found throughout the cAMP pathway with a similar approach, although the authors discovered down-regulation of a newly identified member of this pathway named EPAC2. They suggest these specific changes occurred uniquely in the recovery patients, and were not found in their prior analyses of non-recovery patients. Finally, the authors utilized software that can identify potentially unrecognized interactions between the diversity of genes that were associated with the recovery process. It is interesting to speculate regarding the functional contribution of alterations in the genes and pathways identified by the authors in the recovery process. However, the human recovery model only allows for speculation regarding their functional role. Although the authors indicate some skepticism of animal models, such models will be required to evaluate the functional role of newly identified genes and pathways in the development and regression of heart failure.
Interpretation of the current results should be approached with caution due to extremely limited sample size. While microarray studies are a powerful method to investigate global changes in gene expression, they also require sufficient sample size and appropriate statistical analysis. There are numerous approaches to normalize microarray data and verify its quality prior to analysis, accompanied by several methodologies to assess the false discovery rate among genes identified in subsequent statistical analyses. Perhaps due to sample size, neither data normalization nor false discovery rates are reported, both of which would be important to evaluate the significance of the results. In an attempt to reduce error, the authors combine results from paired and un-paired t-tests, and utilize only genes that overlap both lists for further study. Unfortunately, t-tests, in particular, are statistically weak in small samples with abnormal distribution. The major benefit of studying the recovery patients is the ability to perform paired statistical analysis on the same patients before and after recovery. However, even paired statistics have their sample size limitations. The reported sample size also does not allow assessment of the contribution of numerous other factors such as aetiology, gender, duration of diagnosis and support, role of individual pharmacological agents, etc. to the observed changes in gene expression.
The current study utilized tissue obtained from a single centre, prospective, observational study.9 Patients enrolled in this study received medical therapy with ACE-I, ß-blockade, and aldosterone inhibition followed by a ß2 agonist once regression of left ventricular enlargement had occurred. Ultimately, 11 of the 15 reported patients (24 were enrolled in9) treated with this strategy were weaned from their devices, and seven enjoyed long-term recovery. All of the recovery patients were non-ischaemic, generally young for a heart failure population, and the inclusion of patients with recent onset alcoholic and peri-partum cardiomyopathies likely provided selection bias towards a higher success rate. Further research is necessary to identify the appropriate patient and associated treatment and weaning protocols before these devices in combination with medical interventions can routinely be used as a bridge to myocardial recovery.
Despite numerous advances, several clinical barriers exist to LVADs becoming mainstream destination or recovery therapy for end-stage heart failure patients, including peri-operative mortality, right ventricular dysfunction, infections, thrombo-embolic complications, and device failure. Although technological advances are likely to reduce device failure, other complications may remain formidable obstacles. The International Society for Heart and Lung Transplantation registry recently reported 655 patients who received mechanical circulatory assist devices (mostly pulsatile) January of 2002 through December of 2004.12 Of these, only 35 patients, representing 5% of the population, could be weaned from their device, and sparse follow-up data was reported for these patients. The development of smaller second and third generation devices utilizing both pulsatile and non-pulsatile flow is currently underway.
The optimal medical regimen for reverse remodelling and recovery with assist devices remains unknown, as there are no large prospective, randomized trials of medical interventions in this population. Many centres have adopted standard heart failure therapies such as ß-AR blockade, aldosterone antagonists, and ACE-I for these patients; however, it is unknown how assist devices may modify these effects. Extreme ventricular unloading may contribute to myocardial atrophy and maladaptive foetal gene expression, excessive adrenergic withdrawal may worsen heart failure, and chronic ß1-AR stimulation is deleterious. However, increased ß2-AR signalling by cardiac over-expression of ß2 receptors or by ß2 agonists similar to clenbuterol have been shown to improve cardiac contractility and physiological hypertrophy concurrent with decreased remodelling and apoptosis in animal models of heart failure.13,14 Paradoxically, the current study identifies down regulation of EPAC2 (a component of the ß-AR signalling pathway) in recovery patients. However, recent animal studies have suggested an important role for EPAC in hypertrophic growth of cardiomyocytes,15 and suggest an important role for ß2-AR signalling in physiological hypertrophy and cardioprotection.13,14 Further study of EPAC2 will be required to determine its functional role in the heart.
In summary, the current study provides a preliminary insight into gene expression changes associated with LVAD/clenbuterol-mediated recovery from heart failure in a limited patient population. This should provide the impetus for large multi-centre trials with controlled medical interventions to understand the biology of cardiac remodelling with mechanical support. Study of gene expression, genetics, and genome-wide associations in such a trial could provide further mechanistic insights into the recovery process and potentially identify therapeutic and diagnostic targets. Expansion of sample size in larger, controlled trials and a combination of clinical, genetic and genomic information could one day identify both therapeutic targets as well as a prediction paradigm for individual patient response to mechanical support with targeted pharmacological therapy. Hall et al.8 provides a launching point for such studies.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society Cardiology.
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