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Right arrow Mechanical Circulatory Assistance

Ann Thorac Surg 2003;75:S36-S41
© 2003 The Society of Thoracic Surgeons

Supplement

Bridge to recovery with the use of left ventricular assist device and clenbuterol

Jimmy K. F. Hon, MRCSa, Magdi H. Yacoub, FRSa*

a Department of Cardiothoracic Surgery, National Heart and Lung Institute at Royal Brompton and Harefield Hospitals, London, United Kingdom

* Address reprint requests to Dr Yacoub, Department of Cardiothoracic Surgery, Royal Brompton Hospital, Sydney St, London SW3 6NP, United Kingdom
e-mail: j.hon{at}ic.ac.uk

Presented at the Heart Failure & Circulatory Support Summit, Cleveland, OH, Aug 22–25, 2002.

Abstract

Treatment of heart failure using a left ventricular assist device (LVAD) is emerging as one of the most rapidly expanding areas. These devices are now used to treat patients with terminal heart failure not only as a bridge to transplantation but also for a bridge to recovery in certain carefully selected patients. More recently we have developed a strategy of combining LVAD support with pharmacologic therapies to produce maximal reverse remodeling followed by the induction of physiologic cardiac hypertrophy using clenbuterol, a selective ß2-adrenergic receptor agonist (the Harefield protocol). The purpose of this communication is to provide a brief review of remodeling, reverse remodeling, and the rationale for the use of clenbuterol to enhance the efficacy of the LVAD.

Surgical treatment of heart failure is emerging as one of the most rapidly expanding areas. This expansion is because the disease is having a major and expanding adverse effect on both the survival and quality of life of a significant proportion of society world wide [1] that amounts to several million people yearly coupled with the development of surgical techniques targeting the myocardium. One of the most intriguing and dramatic techniques (when it works) is the use of an implantable left ventricular assist device (LVAD) as a bridge to recovery. These devices were developed to treat patients with rapidly deteriorating terminal heart failure as a bridge to transplantation or more recently as "destination" therapy in patients who are not candidates for transplantation [2]. During the extended use of these devices several seminal observations were made regarding reversibility of heart failure at structural, cellular, molecular, and functional levels through examination of explanted heart at the time of transplantation [3–10]. In addition some patients who had to have the device switched off or explanted for either infection or malfunction were noted to have reasonable or near normal myocardial function for varying periods of time, sometimes over several years [11, 12]. Thus the concept of "bridge to recovery" was born. However concern about the reliability of this technique both in terms of the percentage of patients who might benefit from the procedure [13] and importantly the durability of the recovery prevented the deliberate application of the technique and prompted some authors to describe it as a "bridge too far" [14]. In an attempt to address these two concerns we have developed a strategy of combining LVAD support with pharmacologic therapies to produce maximal reverse remodeling followed by the induction of physiologic cardiac hypertrophy using clenbuterol (the Harefield protocol) [15, 16] thus enabling the explantation of the device and minimizing or abolishing the risk of recurrence of dilation and heart failure. The purpose of this communication is to provide a brief review of remodeling, reverse remodeling, and the rationale for the use of clenbuterol in inducing physiologic hypertrophy.

Remodeling

The progression of ventricular dysfunction is accompanied by changes in all the different components of the myocardium including cardiomyocytes, the extracellular matrix, the coronary vasculature, and fibroblasts leading to alteration in ventricular geometry and myocardial architecture that can be defined as myocardial remodeling. These processes are initially adaptive but invariably lead to ventricular failure. Hypertrophy of cardiomyocytes take place predominantly in the form of cellular elongation relative to the width [17]. Associated with this are the changes in the expression of an array of genes including genes encoding cytoskeletal and noncytoskeletal proteins. The noncytoskeletal proteins include calcium handling proteins, metabolic enzymes, ion channels, cytokines, and growth factors and enzymes involved in apoptosis. The net result of all these is cardiomyocyte contractile dysfunction [15, 18].

The exact mechanism for these changes is not known. It is thought that mechanical stretch is involved in many instances [19]. Activation of the renin-angiotensin-aldosterone system [20], the ß1-adrenergic receptor system [21, 22], and the cytokine and inflammatory pathways [23–25] all play a part. More recently a link between urotensin II, its receptor GPR 14 (now known as the UT receptor), and the cardiac dysfunction and remodeling characteristic of congestive cardiac failure [26] was found. Studies show that human urotensin II causes cardiac dysfunction in mammals, proarrhythmogenic activity in isolated human hearts [27], and increased collagen production in neonatal cardiac fibroblasts, suggesting that congestive cardiac failure might be associated with the myocardial urotensin II system. Another important event in myocardial remodeling is alterations in the extracellular matrix. A family of zinc-dependent proteases implicated in facilitating myocardial tissue remodeling by degrading components of the extracellular matrix are the matrix metalloproteinases (MMPs). The temporal expression of MMPs and the local tissue inhibitors of MMPs (TIMPs) appear to be differentially regulated in several cardiovascular disease states such as myocardial infarction, left ventricular (LV) hypertrophy, and dilated cardiomyopathy [28, 29]. However upregulation of MMPs expression and activity is common in the failing myocardium independent of the underlying disease [28, 30]. Increased collagen deposition seen in diseased myocardium has been proposed to be the result of increased synthesis or decreased degradation and the MMP/TIMP system is thought to play a crucial role in the regulation of collagen turnover. This is supported by recent evidence that showed MMPs inhibition led to the attenuation of left ventricular remodeling and dysfunction in a rat model of progressive heart failure [31]. Apoptosis is also thought to play an important role in remodeling particularly in the transition between cardiac hypertrophy and failure [19, 24].

Using the current gene chip technology for high throughput gene expression analysis [32, 33] together with the use of proteomics [34] we hope to rapidly expand our knowledge of the changes in gene expression associated with remodeling and heart failure further enabling us to more closely target future pharmacologic intervention.

Reverse remodeling

Cardiac remodeling is a bidirectional process through complex pathways termed "reverse remodeling" [35]. In simplistic terms this is a process of recovery or shift toward normality from a previously pathologic state. However the phenomenon of reverse remodeling is poorly understood. In morphologic terms reverse remodeling is associated with decrease in the mean diameter, cell volume, cell length, cell width, and cell length-to-thickness ratio of cardiomyocytes [3–5]. There is also a reversal of cardiac gene expression in advanced heart failure for the atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) [3] and a change in gene expression compatible with an improvement in calcium handling properties [6, 7] and a decreased susceptibility to apoptosis [8, 36]. Other markers of recovery include the downregulation of MMPs and reduction in collagen damage and fibrosis in the failing human heart [5, 9, 37], reduction in myocardial TNF-{alpha} expression [38], and improvement of myocardial mitochondrial function after hemodynamic support with left ventricular assist devices in patients with heart failure [39]. Inflammatory markers of heart failure also seem to be beneficially effected by chronic circulatory support. Goldstein and colleagues [40] characterized the cytokine profile in 14 patients with acute circulatory collapse undergoing LVAD placement and found a significant attenuation of interleukin levels after a period of circulatory support. Functionally reverse remodeling is associated with improvement in myocytes [41] and myocardium contractile strength [6] and overall cardiac performance [10, 38]. In idiopathic dilated cardiomyopathy for example, reverse remodeling was achieved by treatment with ß-blockers resulting in functional improvement closely associated with beneficial changes in myocardial gene expression [42].

In the Harefield protocol [15, 16] maximum reverse remodeling is brought about by the use of LVAD and various pharmacologic agents known to induce reverse remodeling such as ß-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-1 receptor antagonists, and spironolactone. Once maximum reverse remodeling has been achieved the selective ß2-receptor agonist clenbuterol is then used to induce physiologic cardiac hypertrophy as well as improve skeletal muscle mass and function. During this period all the drugs used induce reverse remodeling are continued but ensuring the use of a ß1 selective adrenergic blocker such as bisoprolol so as not to interfere with the action of clenbuterol.

Clenbuterol and physiologic cardiac hypertrophy

There have been concerns about the potential detrimental and regressive changes in cardiac muscle through substantial chronic unloading of the myocardium with circulatory support [43, 44], analogous to skeletal muscle atrophy after long bones fractures. This was certainly one of the reasons suggested to explain the current low incidence of success with ventricular assist device as a bridge to recovery [44]. We believe that for ventricular assist devices to be successful in bridge to recovery protocols, regression of myocardial hypertrophy with all the benefits of reverse remodeling mentioned above brought about by chronic hemodynamic unloading needs to be followed by induction of physiologic cardiac hypertrophy [15, 16] to achieve consistent successful explantation of the device. This strategy is currently being explored clinically in our institution (the Harefield protocol) [15, 16].

The induction of physiologic cardiac hypertrophy without adverse effect like that achieved with exercise training [45] is desirable and clenbuterol, a selective ß2-adrenergic receptor agonist, is known to produce skeletal muscle hypertrophy [46–48]. In addition clenbuterol has also been shown by our group to induce cardiac hypertrophy in rats with molecular and functional indicators consistent with physiologic cardiac hypertrophy [22, 46]. Unpublished data from Bhavsar and colleagues at our institute has demonstrated marked cardiomyocyte hypertrophy when neonatal rat cardiac myocytes were stimulated with clenbuterol for 48 hours (Fig 1). Petrou and colleagues [46] and Wong and associates [22] both showed that clenbuterol stimulated left ventricular hypertrophy with physiologic molecular phenotype (eg, elevated levels of mRNA to atrial natriuretic factor without a concomitant increase in skeletal {alpha}-actin and ß-myosin heavy chain and normal expression of sarcoplasmic reticulum Ca2+-adenosine triphosphatase-2a [SERCA2a] and phospholamban mRNA) in an otherwise healthy normal rat heart. As shown in Figure 2, the amount of fibrosis in the clenbuterol induced hypertrophied heart is also normal [22]. This is in distinct contrast to the pathologic hypertrophy caused by isoproterenol. In addition Wong and colleagues [49] also documented the ability of clenbuterol to transform pathologic functional and molecular markers in the pressure-overloaded hypertrophied left ventricles towards normality (eg, improvements in the SERCA2a mRNA level and normal collagen concentration in clenbuterol treated hearts in association with improved systolic and diastolic function). More recently Hon and colleagues [50] from our group has demonstrated using pressure-volume analysis that clenbuterol improved the systolic function of the right ventricle of sheep after six and a half weeks of pulmonary artery banding as illustrated in Figure 3.



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  		Fig 1. Neonatal rat cardiac myocytes untreated (top) or stimulated with clenbuterol for 48 hours in culture followed by staining with an antibody to {alpha}-actinin. Those treated by clenbuterol (bottom) appear much larger. (Figure kindly provided by Dr Pankaj Bhavsar.)

 


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  		Fig 2. Representative left ventricle sections stained with hematoxylin and eosin demonstrating morphology in clenbuterol-treated hearts (b) and thyroxine-treated hearts (c) to be similar to that of controls (a). In contrast isoproterenol-treated hearts (d) showed characteristic myocyte necrosis with collagen replacement in these areas. Scale bar = 0.25 mm. (Reprinted with permission from Wong K, et al. Cardiovasc Res 1998;37:115–22.)

 


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  		Fig 3. Ovine right ventricular end-systolic pressure-volume relations of pretreatment (no pressure overload) and post-treatment with clenbuterol. Note the higher diastolic pressure post-treatment due to presence of chronic pressure overload by pulmonary artery banding. Systolic ventricular function was improved despite the presence of pathologic hypertrophy.

 
All these reports on clenbuterol have been consolidated by communications from various other groups reporting the beneficial functional effects of ß2-adrenergic receptor overexpression in mouse hearts [51–53]. One in particular showed that the positive effects of ß2-adrenergic receptor on cardiac function is prolonged as long as a certain "threshold" of receptors overexpression is not exceeded [53]. It has also been shown that ß-adrenergic receptor mediated apoptotic death signaling is largely dissociated from ß2-receptors and selectively mediated by ß1-receptors in adult rat ventricular myocytes [21]. Using a gene transfer technique Tevaearai and colleagues [54] elegantly demonstrated that overexpression of ß2-adrenergic receptors potentiated the functional recovery of unloaded failing hearts, directly supporting our concept for using the combination therapy (the Harefield protocol). On the background that most of the toxic effects of ß-adrenergic stimulation appears to be mediated largely by the ß1-adrenergic receptors, it will be reasonable to speculate the potential benefits of the concurrent usage of ß2-adrenergic receptor agonist like clenbuterol together with a selective ß1-adrenergic receptor antagonist in clinical settings.

The growth-promoting effects of clenbuterol on skeletal muscle and its ability to act as a repartitioning agent has previously been described [46–48]. Petrou and colleagues [46] showed that the body weight increase produced by clenbuterol treatment was associated with skeletal muscle hypertrophy and a reduction in body fat (repartition). As shown in Figure 4, the hypertrophied skeletal muscle is capable of stronger and faster contractions [47]. There have been suggestions that clenbuterol-induced skeletal muscle hypertrophy could be mediated by local production of insulin like growth factor-1 (IGF-1) [55]. An elegantly performed experiment by Musaro and colleagues [56] reported a model of persistent functional myocyte hypertrophy through a tissue-restricted transgene encoding a locally acting isoform of insulin-like growth factor-1 that is expressed in skeletal muscle (mIgf-1). In their report marked hypertrophic myocytes were seen and these myocytes escaped age-related muscle atrophy and retained the proliferative response to muscle injury characteristic of younger animals.



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  		Fig 4. (A) Pressure augmentation. Control muscles (open circles) and clenbuterol-treated muscles (diamonds; bottom line) fatigued within 5 minutes. At 60 minutes clenbuterol plus trained skeletal muscle (inverted triangles; upper line) generated greater augmentation per contraction than the trained-only group (squares; middle line). (B) Representative pressure waves. (C) Stroke power. *p less than 0.05. Note: logarithmic scale was used on vertical axis. (Reprinted from Petrou M, et al. Circulation 1999;99:713–20.)

 
This dual ability of clenbuterol to induce physiologic myocardial growth and skeletal muscle growth is potentially desirable; as many patients with terminal heart failure requiring ventricular assist are in cachetic state, the benefits of using clenbuterol in these patients are apparent.

In the Harefield protocol clenbuterol treatment was initiated when maximal regression of the left ventricular end-diastolic and end-systolic diameters have been reached and when these have been stable for at least 2 weeks. Treatment was started at small doses of 40 µg twice a day rising to 700 µg three times a day. The duration of treatment was variable and treatment was usually continued until the explantation criteria has been reached.

The future

It is concluded from our experience that the combination therapy for reverse remodeling followed by induction of physiologic cardiac hypertrophy is a very promising strategy in patients with end-stage heart failure. This needs to be actively explored in different groups of patients initially in those with idiopathic dilated cardiomyopathy and possibly extending its use to ischemic cardiomyopathy in the future. A large number of patients could benefit from the combination therapy while others could be considered for additional emerging therapies such as gene therapy, cell transplantation, or a combination of those.

Acknowledgments

The authors gratefully acknowledge the contributions of the members of the LVAD Research Group for data included in this article. In particular we would like to thank Dr Pankaj Bhavsar for providing Figure 1. This work was supported by the Harefield Research Foundation, Royal Brompton and Harefield Charitable Trustees, and the British Heart Foundation.

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