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Myocardial recovery: a focus on the impact of left ventricular assist devices Expert Rev. Cardiovasc. Ther. 12(5), 589–600 (2014)

M Scott Halbreiner1, Vincent Cruz2, Randall Starling3, Edward Soltesz1, Nicholas Smedira1, Christine Moravec3 and Nader Moazami*1 1 Cleveland Clinic Foundation, Thoracic and Cardiovascular Surgery, Cleveland, OH, USA 2 Cleveland Clinic Lerner College of Medicine, 9500 Euclid Avenue, NA-21, Cleveland, OH 44195, USA 3 Cleveland Clinic Foundation, Cardiovascular Medicine, Cleveland, OH, USA *Author for correspondence: Tel.: +1 216 444 6708 [email protected]

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Heart failure remains one of the most prevalent diseases worldwide and in recent decades, left ventricular assist devices (LVADs) have become an important treatment option. With increasing device experience, there is particular interest in the use of LVADs as a bridge to recovery that allows the patient’s heart to undergo reverse remodeling, whereby the device can be explanted and the heart can function at an improved state. There are many considerations that play a role in this process, including the ability of the device to unload the heart, the innate physiology of the heart to recover and the use of concomitant therapies. This review provides an overview of the most current literature as it pertains to these processes and gives a view into the future directions of LVADs as a tool for achieving myocardial recovery. KEYWORDS: heart failure • myocardial recovery • ventricular assist devices • ventricular recovery • ventricular remodeling

Heart failure (HF) is one of the most prevalent diseases with an estimated 6 million people in the USA currently diagnosed with the disease, and it is predicted that by the year 2030 around 10 million people will be affected. HF patients tend to present in their sixth decade of life and typically have had a previous myocardial infarction or an extensive history of hypertension. It is seen more often in African–Americans, which is likely due to the higher number of risk factors in this population, including diabetes mellitus, obesity, smoking and high cholesterol [1]. Half of the people diagnosed with end-stage HF die within 5 years of diagnosis, and HF is the contributing cause in one out of nine deaths [2,3]. A major concern with the increasing number of patients diagnosed with HF is the large economic burden. CDC statistics report that the USA spends about $32 billion every year in healthcare-related services [4]. There is a very broad list of pathophysiological mechanisms that lead to HF, and most patients will likely have multiple contributing factors [5]. The process that leads to end-stage HF is thought to involve progressive adverse remodeling (AR) of the myocardial tissue that occurs as a result of compensatory responses. The key clinical components of AR are important to understand. Butler described them as

10.1586/14779072.2014.909729

neurohumoral upregulation, myocyte hypertrophy, remodeling of the extracellular matrix (ECM) and a proinflammatory milieu [6]. Because of this complex array of etiologies and underlying mechanisms, there are multiple medical therapies each designed to target particular pathophysiological mechanisms. Pharmacotherapy for blockade of the adrenergic system, modulation of the renin–angiotensin axis, aldosterone antagonism and cardiac resynchronization therapy have been the subject of multiple trials showing improvement in survival. In this review, we explore how left ventricular assist devices (LVADs) similarly can target various AR mechanisms to promote reverse remodeling (RR). The focus will be on the current clinical understanding of the role of LVADs in restoring cardiac function, at the clinical and molecular level, and if that may translate into a sustained paradigm for cardiac recovery. Shortcomings of heart transplantation & mechanical circulatory support

Transplantation is considered the gold standard for the treatment of end-stage HF. Transplantation results in reasonable survival of up to 70% at 5 years. The ‘half-life’ of a heart is currently about 11 years overall and improves to 13 years for those who survive the


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first year [7]. The number of heart transplants in the USA has remained relatively steady over the last decade with approximately 2100–2200 a year. At the same time the number of new adults on the active transplant list has increased by nearly 20% since 2004, with roughly 3700 individuals on the list currently [8]. Waiting time to transplant for candidates listed in 2010–2011 was 3.8 months longer than those listed during 2006–2007 [9]. Beyond scarcity, heart transplantation is far from ideal. Advanced age has now been identified as an independent risk factor for mortality after transplant despite many older adults being transplanted [7]. The proportion of heart recipients between the ages of 60 and 69 has increased from 14% between 1982 and 1995 to 24% between 2006 and 2012 [7]. Cumulative morbidity rates within the first 5 years after transplant are sobering: nearly all recipients have hypertension (92%) or hyperlipidemia (88%), while roughly half have renal dysfunction (52%) and a third develop either cardiac allograft vasculopathy (30%) or are found to have diabetes (38%) [7]. Aside from these limitations, transplantation requires lifelong immunosuppressive therapies. Despite great advances in development of new drugs and the low rejection rates, there are significant side effects from these regimens, including renal toxicity from calcineurin inhibitors and various untoward effects from chronic steroid use. The promise of LVADS as an alternative option to transplantation has been the driving force in application of these devices as destination therapy [10]. Nevertheless, with increasing number of patients on LVADS, the significant cumulative short- and long-term morbidity of this therapy is being realized; specifically those related to gastrointestinal bleeding, infections, device malfunction, strokes and pump thrombosis [11]. Kirklin reported an interval analysis of Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) data showing that bleeding occurred in 41.6%, infection in 40%, device malfunction in 12.8%, venous thrombotic events in 5.7% and arterial thrombotic events (including pump thrombosis) in 2.5% [12]. Clinical reports of RR with LVADs coupled with the shortcomings of transplantation and clinical adverse events associated with long-term therapy have stimulated an emerging interest in use of devices as an adjunct to other therapies to promote RR and ventricular recovery. The literature on RR with LVADS is diverse in terms of the types of devices used. In the earlier experience, most of the data was related to pulsatile flow pumps (PF). Although these pumps were asynchronous with the heart beat, they worked based on the concept of ‘fill to empty’ and allowed both pressure and volume unloading of the heart. In the past decade, continuous flow (CF) pumps have dominated the field and this may have different implications on RR. These pumps work primarily by generating CF by means of a rotor element. Thus during the entire cardiac cycle, continuous unloading of the left ventricle occurs. It has been shown that in both types of devices there is a reduced end systolic volume, yet PF devices result in a greater reduction in left ventricular end diastolic 590

volume and end systolic volume in addition to a significant reduction in the left ventricular (LV) mass [13]. With CF devices the aortic valve remains closed and thus alters the pressure– volume curves while the PF devices maintained closer to normal physiological LV pressure–volume curves. In some studies, postoperative ejection fraction (EF) and serum markers indicated that PF devices had higher ventricular function and improved ventricular healing [14]. In reviewing the data on RR, it is important to note that the impact of PF versus CF pumps and the different physiological states induced by these two modalities may be challenging to discern. Physiological impact of LVADs on RR

Numerous studies over the past 30 years have shown that support of the failing human heart with an LVAD causes some reversal of the HF phenotype. This has been called ‘RR’ because the response to increased pressure and volume loading in the heart is ‘remodeling’. The increased wall stress that begins the downward spiral of HF initiates a cascade of cellular and molecular alterations that produce changes in the size, shape and function of the ventricle by remodeling its cells and their connections to one another. When it became clear that the LVAD was capable of reversing these changes, that process was called ‘RR’. It is important to fully investigate the RR process for two reasons. The first, and the one that usually limits discussion, is that the LVAD might result in recovery from HF. There is, however, a second and perhaps fundamentally more important reason to study the process of RR – to fully understand the plasticity of the heart, or what degree of cellular and molecular reversal is possible in heart cells. End-stage HF has for years been deemed irreversible, leading to the inevitable conclusion that transplantation is the best therapy. Studies of RR, made possible by tissue removed from LVAD-supported patients, have allowed us to discover that the biological change occurring within heart cells in response to increasing wall stress is not irreversible. We do not yet know whether these cellular and molecular reversals are associated with recovery or which of them is most important because for the first few decades of the LVAD experience, tissue was available only at the time of LVAD implant and at the time of explant for transplantation. Studies showed cellular, molecular and functional change at the tissue level between implant and explant, but the tissue samples came from patients who had heart transplants, and thus the findings could not be said to correlate with myocardial recovery. More recently, a second phase has begun, in which tissue from patients who have the device explanted for recovery is available for cellular and molecular investigations [15]. This approach may lead to a more rapid understanding of the relationship between cellular and molecular remodeling and clinical recovery. Geometry

Among the first significant changes reported following initial LVAD implants, and one that led very early to speculation about ‘RR’, was the robust decrease in the size of the failing heart once it was hemodynamically unloaded [16–21]. Echocardiography in Expert Rev. Cardiovasc. Ther. 12(5), (2014)

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the operating room allowed for measurement of an early change in LV size and volume [16], which in many cases persisted until explant for transplantation [17,19]. In fewer cases, the LVAD was explanted, the patient recovered and the size and shape changes in the left ventricle persisted for years [20,22]. In most patients, left atrial size also decreased with LVAD [17], pressure–volume loops confirmed lower volumes at similar pressures with the LVAD in place [16,17] and the heart returned to a more normal, elliptical shape, from its failing spherical shape [20]. These size and volume changes were shown for pulsatile LVADs some years ago and have been reported more recently for CF LVADs [18,21,23], although some disagreement remains about the extent of unloading and the resulting remodeling with the two types of LVAD [17,18]. These studies have collectively shown that even in the most severe HF patients, with extreme dilation of the ventricle, hemodynamic unloading with an LVAD is capable of normalizing cardiac size and shape. Studies of LVAD-induced changes in chamber size have generally been done while the LVAD is fully unloading the heart, but more recent turn-down studies have revealed that persistent changes in size are predictive of recovery after explant [17,22,24,25]. Contractility

Simultaneously with normalization of size and shape, LVAD support was shown to improve LV function, demonstrated by increased EF, increased cardiac output and improved exercise tolerance [17,19,21,26,27]. These improvements were demonstrated for both PF and CF devices, and occurred regardless of HF etiology [27]. Tissue removed at LVAD implant, as well as the whole heart when explanted prior to transplant or a small piece when the LVAD was explanted for recovery, became valuable tools for translational research. Scientists were able to demonstrate that which had been harder to prove in vivo – that the cardiac muscle itself, studied in isolation in the laboratory, actually improved its ability to contract and relax after hemodynamic unloading with an LVAD [19,28–31]. These experiments were done in two ways: comparing muscles taken at transplant from patients supported by an LVAD to muscles from patients not supported by an LVAD and comparing muscle from patients at LVAD implant to muscle from the same patients at LVAD explant [28]. Data from both approaches demonstrated improved contractile function, including improvement in the force–frequency relationship [17] and post-rest potentiation [28], both diagnostic of impaired contractile function in human HF. The finding was extended to individual cardiac myocytes using the same approaches [19,28,31]. Although many studies have shown improved contractile function of both muscle strips and myocytes after LVAD, it is worth noting that a recent study, using skinned cardiac myocytes (and thus able to assess contractile protein function and activation by calcium without the confounding effects of membranes and signaling pathways), showed that the recovery of contractile function after LVAD remained below the levels measured in myocytes from nonfailing hearts and that only one protein of the many involved in the regulation of contraction informahealthcare.com

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(TnI) was changed after LVAD [26]. This study was more sophisticated in its methods and analysis than earlier studies of contractile function and calcium sensitivity after LVAD support, and it suggests that recovery of contractility may not be an ‘all-or-none’ phenomenon even if some recovery has been demonstrated. The authors suggested that additional interventions may augment the unloading provided by LVAD, but it is clear that further studies will be needed to fully elucidate the effects of hemodynamic unloading on contractility of cardiac muscle and the individual contractile proteins. It is also worth noting that, in addition to the contractile proteins, force generation in cardiac muscle relies on an intact and properly functioning cytoskeleton, maintaining the structural integrity of the sarcomere and allowing muscle cells to shorten and re-lengthen. Studies have suggested alterations of many cytoskeletal proteins in human HF and recovery of some with LVAD support [15,21,28]. These include proteins such as dystrophin, vinculin, integrins, tubulin and titin. Given the complexity of the myocyte cytoskeleton, and the number of molecules involved, further studies will be needed to elucidate the regulation of this important component of myocardial structure and function. Examination of tissue removed during LVAD explant for recovery has hinted that a particular pattern of protein remodeling, both sarcomeric and cytoskeletal, may help to predict recovery [15,16,20,28], and the integrins in particular have been singled out as having the potential to play a significant role in RR [15,28]. Histology

When early LVAD studies revealed improvements in size, shape and cardiac function, attention turned to histological investigation, asking whether the individual heart cells or their intracellular contractile structures had changed. Along with the decrease in chamber volume and mass and a shift in the pressure–volume relationship, tissue studies showed that individual myocytes were smaller after LVAD support [17,29–31]. This was supported by studies in cells isolated from the tissue samples, where a reduction in cell capacitance was measured as an index of cell size [16]. Detailed investigation revealed decreases in cell length, width and area [17,32], and suggested that changes in cell dimensions might relate to duration of unloading [32]. It has been shown that changes in cell size are unique to the left ventricle after LVAD, suggesting that the stimulus for such changes is loading conditions rather than circulating factors [29]. Importantly, it is not clear that reduction in cell size following LVAD correlates with clinical improvement. Comparing tissue from patients who had a transplant after LVAD support to those who had the LVAD explanted for recovery demonstrated that cell size changed equally in both groups [15]. Besides changes in cell size, the investigators reported decreases in contraction band necrosis, myocytolysis and the ‘waviness’ of sarcomeres following LVAD support [17], while others have suggested that reduction in cell size is actually accompanied by greater sarcomeric disarray than that observed in the failing heart [17]. A decrease in apoptosis has been observed following 591

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LVAD [15,19,32], as has an increase in the proportion of multinuclear cells [17,29]. Markers of autophagy have been shown to be decreased [19]. There has been much speculation that complete unloading or unloading that persists for long periods of time may result in atrophy of the myocardium [17,20,28], but robust histological evidence for atrophy is lacking.

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Calcium handling

With a smaller, more functional heart characterized by normalized cell size and improved contractility, attention turned to intracellular calcium cycling. Calcium signaling is vital in the regulation of myocardial contraction and relaxation, and is tightly regulated within narrow limits by a system of release and reuptake into the cytosol from storage in the sarcoplasmic reticulum and from the extracellular space [33]. Any disruption in intracellular calcium cycling results in impaired contraction and relaxation, and numerous studies have shown that the processes are defective in human HF [17,28]. Studies in tissue explanted from LVAD-supported patients rapidly demonstrated reversal of some of the key abnormalities associated with HF, including the action potential, intracellular calcium transient [17,19,28,32], sarcoplasmic reticulum calcium store [16,19,28,32] and proteins such as the sarcoendoplasmic reticulum calcium ATPase and its regulator, phospholamban, as well as the sarcolemmal sodium-calcium exchanger and the ryanodine receptor [17,19,28,29,32]. Studies have suggested that calcium handling is affected by LVAD support duration – shorter durations of support produce recovery of calcium regulatory proteins and their functional correlates, but these changes go back to failing levels following longer support durations [28]. While calcium cycling can be affected by neurohormones, data show that the changes in calcium cycling proteins occur only in the left ventricle after LVAD, suggesting a role for hemodynamic support rather than the decrease in circulating neurohormones as the stimulus for these changes [17]. Given the importance of intracellular calcium cycling in controlling myocardial function, it is important to ask what happens to calcium cycling in patients who recover and are able to have the LVAD explanted. To date those studies have shown the largest improvements in action potential duration and in sarcoplasmic reticulum calcium content in tissue from the recovered patients [15,28], indicating that reversal of calcium cycling, and sarcoplasmic reticulum function in particular, may be a key component in myocardial recovery [15,28,32]. Given the success with the CUPID trial [33,34], which attempts to restore calcium cycling via gene therapy, data show that LVAD support normalizes calcium cycling in patients who recover could be a reason for optimism. b-adrenergic system

Although intracellular calcium cycling regulates myocardial contraction and relaxation under resting conditions, the heart during its transition to failure recruits several compensatory mechanisms. Chief among these is the sympathetic branch of the autonomic nervous system, which attempts to compensate 592

for decreased cardiac output by stimulating both the rate and the force of contraction, in addition to increasing vasodilation and tissue perfusion, all through the actions of neurohormones on adrenergic receptors. While this response is compensatory and at first adaptive, excess circulating catecholamines cause downregulation of b-adrenergic receptors on the myocardial cell surface and eventually this contributes to the downward spiral of HF [35]. Downregulation of b-adrenergic receptors and a decrease in the resulting inotropic response of cardiac muscle is so well established in HF that it has become a marker of the HF phenotype, and studies of RR naturally sought to include the fate of b-adrenergic receptors and their signaling pathways. LVAD support of the failing human heart has so far been shown to normalize b-adrenergic receptor density, the localization of receptors within the cell, adenylyl cyclase activity, inhibitory G protein levels, the PI3K pathway that mediates downregulation of the receptors and the response of isolated muscle to stimulation with agonists [17,19,27,29,31]. The stimulus for RR of the badrenergic signaling pathway could be hemodynamic unloading, but it may also involve a decrease in circulating neurohormones, shown to occur after LVAD therapy [17]. The RR described in the preceding paragraph has been measured in patients who were supported by an LVAD prior to heart transplant. More recently, information on patients who have been bridged to recovery by an LVAD has become available. Although more work is needed and observations made at the mRNA level must be confirmed with protein and functional analysis, the first studies to report results of b-adrenergic signaling reversal in patients who recovered suggest that elements of this pathway are associated with recovery [28]. Extracellular matrix

The ECM includes the proteins that connect myocytes to one another. In the heart, the ECM includes proteins such as collagen and fibronectin. More controversy has surrounded the ECM and its potential for remodeling after LVAD than any other portion of the myocardium. It has been known for decades that excess wall stiffness limits relaxation in the failing heart, and ECM proteins have been associated with this stiffness either because their production increases, their turnover decreases or they are excessively cross-linked [27,36]. From the beginning, studies of myocardial collagen content following LVAD support suggested that collagen actually increased following unloading or that its cross-linking increased [19,20,28]. Other studies suggested that fibrosis decreased with short-term support but increased after longer durations, suggesting a relationship between duration of unloading and collagen turnover [17,19,27]. Sophisticated microscopic techniques have recently been used to quantify fibrosis throughout the thickness of the ventricular wall, and these studies have revealed an increase in fibrosis following LVAD, although it is not clear whether this indicates a failure of reversal or simply progression of the disease in spite of the LVAD [19]. In the normal heart, there is a balance between the matrix metalloproteinases and their tissue inhibitors that regulates collagen turnover. Several Expert Rev. Cardiovasc. Ther. 12(5), (2014)

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studies have shown that this balance is altered in HF and may be further altered in hearts supported by LVAD [17], changing the relationship between collagen production and collagen breakdown. Again, these changes seem to occur primarily in the left ventricle, suggesting hemodynamics as the regulating stimulus. At least one study has suggested that the older, pulsatile LVAD may be more successful at improving both serum and tissue markers of ECM turnover than the newer pulsatile devices [18], but this remains to be confirmed. The ECM, perhaps more than other myocardial constituents, is regulated by the renin–angiotensin system, and thus may be altered in patients taking angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers. It was noted by some investigators that patients supported by LVAD were frequently not taking ACE inhibitors, and several studies have shown that the addition of ACE inhibitors to the therapeutic regimen reverses at least some of the excess fibrosis [17,28]. This suggests that the pharmacological strategy that accompanies LVAD support may play an important role in the RR process [20] and may lend support to an approach such as the Harefield Protocol, delivering a fixed combination of drugs to every LVAD patient [16]. It is clear that in those patients who experience excess fibrosis following LVAD, this is a maladaptive aspect of remodeling and limits myocardial recovery [28]. Several studies have suggested that fibrosis at the time of LVAD implant, measured in the apical core tissue, predicts recovery of cardiac function and LVAD explant [37,38]. It has also been shown that the expression of profibrotic genes prior to implant predicts less recovery [16]. Understanding of the ECM and its potential for RR is in the very early stages, measured to date using protein quantitation, gene expression and some microscopy, with few studies attempting to unravel the complexities of the 3D ECM and the complex regulation of the scaffold that holds myocardial cells together and likely has a role in signaling. This is an area where much work will be needed in the future. Metabolism

Needing to contract and relax 60–80 times per min, cardiac muscle demands a high supply of energy, and thus is more reliant on ATP than many tissues of the body. Anything that interferes with ATP generation becomes limiting for the heart very quickly. The majority of ATP generation in the heart comes from oxidative phosphorylation in cardiac mitochondria, with a small amount provided by anaerobic glycolysis [39]. HF is characterized by severe metabolic alterations, in which fatty acid metabolism decreases, glucose use increases and mitochondrial dysfunction has been demonstrated [39]. Oxygen consumption may be abnormal, phosphocreatine and creatine kinase are depleted [15], and ATP production is compromised. Autophagy, normally responsible for degrading damaged organelles and misfolded proteins, is increased, possibly due to an increase in total protein production within the cell [39]. In order to cause not only RR but also recovery, LVAD support must produce changes in energy metabolism in the direction of normal. informahealthcare.com

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Relatively few studies have investigated the metabolic consequences of LVAD support. Isolated mitochondria from the heart tissue of patients supported by LVAD have demonstrated improved respiration [17], and studies have shown that nitric oxide may play a role in improving mitochondrial function during LVAD support [15,17]. Cardiolipin, a component of the mitochondrial membrane that is important for ATP production, normalizes after LVAD support [15,19,28]. Several genes and proteins related to metabolism, including arginine:glycine aminotransferase, involved in creatine synthesis, and uncoupling protein 3 involved in free radical formation, have been shown to reverse after LVAD [15,28]. Recent studies have demonstrated that LVAD implant improves whole body insulin resistance, decreases toxic lipid intermediates that can have harmful effects on the heart muscle, reverses macrophage infiltration of adipose tissue, reduces inflammation and reverses adiponectin resistance [40,41]. Thus, both systemic and local metabolic derangements characteristic of HF have shown reversal following LVAD unloading of the heart, suggesting plasticity in the heart’s metabolic pathways and potential for RR. Similar to other aspects of the HF phenotype discussed above, some elements of the metabolic pathways have been associated with recovery, measured in those patients from whom the LVAD can be removed successfully and recovery sustained. Arginine:glycine aminotransferase was more significantly downregulated in hearts, which showed recovery after LVAD [15,28], and recovery from low IGF-1 levels also distinguished patients who recovered from those who did not [28]. More numerous and more sophisticated studies will likely be needed in order to fully understand the metabolic rearrangement that accompanies HF and the potential to reverse these changes with mechanical unloading. Gene expression

With the advent of microarray technology, large-scale efforts were made to examine the hypothesis that LVAD-induced remodeling should include groups of genes that are either upregulated or downregulated in response to hemodynamic changes [28,29,31]. In general, microarray studies, performed using both group comparisons (failing hearts with LVAD versus failing hearts without LVAD) and paired comparisons (tissue from the same patient before and after LVAD), have confirmed that genes that improve cardiac function are upregulated by LVAD support [30]. Genes for proteins that regulate calcium cycling, b-adrenergic signaling, metabolic pathways and proteins of the ECM have changed in the directions predicted by earlier studies, although each microarray study has presented slightly different results [28,29,42], and no firm agreement has been reached on which sets of genes are actually regulated by hemodynamic load. Most studies have been done on patients who received a heart transplant, thus limiting the association of any changes in gene expression with recovery. Genes known to be upregulated in HF, such as brain natriuretic peptide and inflammatory markers, have been shown to be downregulated by LVAD. One microarray study examined tissue 593

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taken from patients who demonstrated recovery and successfully had the LVAD explanted. This study, although the sample size was quite small, revealed that recovery after LVAD was associated with significant changes in both the b-adrenergic signaling pathway and the calcium regulatory gene Epac2, in addition to several sarcomeric proteins and cytoskeletal proteins [28]. This microarray recovery study also suggested a significant role for integrins, which transduce stretch signals from outside of the cell to the cytoskeleton. While all of the genes mentioned above code for proteins that actually participate in myocardial function, studies have also identified a number of key regulatory molecules in the heart as being impacted by LVAD support. These include glycogen synthase kinase 3b, a negative regulator of hypertrophy, and NF-kB, a transcription factor controlling many cellular processes during remodeling [42]. The advantage of microarray studies is that they identify a large network of genes that may be simultaneously regulated and thus have the potential to more rapidly expand our understanding of gene regulation after LVAD. The disadvantage is that they produce a large amount of data that must be sorted through and examined for clinical and scientific significance, and we are still learning about how best to use these techniques to clear advantage. Although microarray techniques are powerful and produce much data, they measure mRNA levels, which can lead in the direction of protein, but do not necessarily correlate with changes in the functional protein. At least one recent study has employed proteomic methods to examine tissue before and after LVAD support [43]. Proteomics generally relies on 2D gel electrophoresis and, while more advanced than individual immunoblots, does not provide the same large number of comparisons that microarray technology provides. On the other hand, the analysis provides data on proteins, which are one step closer to cellular function than transcripts. Proteins found to be regulated by LVAD in both ischemic and nonischemic patients included those of the cytoskeleton, those involved in mitochondrial energy metabolism and the serine protease inhibitor a-1-antichymotrypsin. Ischemic and nonischemic etiologies showed some differences in protein levels, most notably in ATP synthetase, downregulated by LVAD in nonischemic patients and upregulated in the ischemic group [43]. This study verified the utility of proteomics in the LVAD patient population, and it is hoped that future studies will investigate proteomic correlations of LVAD explant for recovery. As newer technology and better understanding of gene expression and its regulation evolves, the effects of LVAD support continue to be investigated. miRNAs are noncoding, relatively small RNAs that regulate the function of mRNA by stimulating degradation or inhibiting protein translation [17]. miRNA can be upregulated or downregulated, modifying the function of mRNA. Several recent studies have attempted to test the hypothesis that miRNA might participate in LVADinduced remodeling [44,45]. Various miRNAs have been shown to be upregulated in HF [44], and it has been suggested that the combination of mRNA and miRNA may be the most useful combination for understanding gene regulation, during HF and 594

after LVAD [44]. One miRNA study compared patients in whom the LVAD could be explanted for recovery and those in whom it could not be explanted, looking for a miRNA signature for recovery [45]. Several miRNA markers, together with cell size, at the time of LVAD implant were found to predict functional recovery [45]. Much remains to be done in this field, including a better understanding of the role of miRNA, but these studies are encouraging because they demonstrate that as new technology evolves, that technology is being brought to bear on our understanding of cardiac disease and the potential for RR. Clinical reports of recovery with LVADs

Bridge to recovery (BTR) can be formally and clinically defined as sustained recovery of cardiac function allowing explantation of the device without transplant or recurrence of HF [46]. The proposed biomechanical and molecular changes induced by LVADS as described previously will only be beneficial if they translate into actual clinical recovery. Clinical observations of cardiac recovery in patients with LVADs were described as early as 1996, but more current data tend to represent cardiac recovery better as the devices implanted over the last decade are most often continuous-flow as opposed to earlier studies that look at pulsatile-flow devices [47,48]. Many centers report the successful rates of BTR somewhere around 5% [6], and a 2009 analysis of INTERMACS data reported that of the patients with initial BTR implantation, only 3% had successful recovery with pump removal [12]. Many significant biological outcomes are seen over and over again in studies; however, there seems to be a disconnect between those and the clinical outcomes measured and could be related to limitations in study design or the lack of understanding of the important biological aspects involved in myocardial recovery [19]. Nevertheless, clinical studies have been able to provide a wealth of information regarding how we treat and manage HF patients with LVAD devices in attempt to recovery. ICM versus NICM

Although attempts are ongoing at using LVAD therapy to recover myocardium from ischemic causes of cardiomyopathy, there are significant differences in the reported rates of BTR between those from nonischemic and ischemic cardiomyopathy. Nonischemic causes fare much better than ischemic with BTR rates of approximately 21 and 5%, respectively [6]. More promising candidates for BTR therapy are those with idiopathic cardiomyopathy, hypertensive cardiomyopathy, postpartum cardiomyopathy, myocarditis or any other nonischemic cause. Infarcted myocardium lacks viable cardiomyocytes, and therefore there is not adequate substrate for LVAD support to allow regeneration or RR [49]. However, patients with ICM involving a large area that has remodeled over years may be considered candidates for myocardial recovery efforts [21]. CF versus PF devices

There are important differences seen between continuous-flow and pulsatile-flow devices that are related to the differences in Expert Rev. Cardiovasc. Ther. 12(5), (2014)

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the device’s ability to unload the left ventricle. Kato et al. were able to demonstrate differences in myocardial structure and function [18]. Serial echocardiography showed that patients with a PF device had significantly better systolic and diastolic function and circulating levels of brain natriuretic peptide, and matrix metalloproteinases-9 were more significantly decreased [18]. Even though there is improvement in function and myocyte size in the left ventricle, there is only a partial recovery of EF and myocardial contractility. Ambardekar et al. showed that in a small sample of patients who had nonischemic cardiomyopathy, although there was a significant change in EF after LVAD removal (prior to transplantation) from 10 to 26% (p = 0.007), this was only a partial recovery and the biochemical properties of the sarcomere did not change [26]. There are limited data regarding rates of recovery with CF LVAD support. One analysis of 1108 patients with a HeartMate II (HMII) LVAD showed a sustained recovery rate of 1.8% [50]. Other factors may play a role in this poor recovery rate, including a systematic HF treatment regimen such as the Harfield protocol, discussed later. Another study enrolling CF devices showed recovery rates closer to 60% using a concomitant HF protocol; however, 66% of these patients had 5 years, were at 64 times greater risk of HF recurrence within 3 years from explantation [6]. A longer period of LVAD support is associated with a higher rate of recovery. Drakos et al. report maximal improvement in LV function within 6 months of circulatory support, and recovery has also been reported in patients with peripartum cardiomyopathy after 6 months of LVAD support [24]. Malliaras et al. suggest that unloading of the heart for more than 3 months is required, along with optimal medical treatment, to achieve sufficient recovery [49]. However, cardiac improvement associated with longer mechanical unloading must be balanced against concerns of potential cardiomyocyte atrophy. A multicenter study by high-volume institutions found that after 30 days there was significant LVEF improvement, but a progressive decrease occurred beyond that with no difference in preLVAD measurements by 120 days and histological findings of myocyte atrophy and decreased collagen content [52]. Freedom of recurrence

The ability to maintain myocardial function after LVAD explantation is a critical component of treatment. The incidence of recurrence of HF after explantation has a wide range in multiple studies from 0 to 80% [49]. Yacoub et al. had 1and 4-year freedom from recurrence rates of 100 and 88.9%, respectively, after long-term LVAD support and device explantation [53]. Drakos et al. saw no decrease in LV function at long-term follow-up in their patients, which was carried out to informahealthcare.com

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1 year [21]. TABLE 1 summarizes the results of various studies that include freedom from recurrence that can be seen to be widely variable. Limitations Concomitant management & protocols

One of the more important parts of the use of LVADs for BTR and a key to successful recovery is the concomitant medical treatment of HF. Neither sole mechanical support nor sole medical therapy is nearly as good as the combination of the two therapies. One significant reason that prevents most of the current clinical studies from producing consistent results is that there is no particular agreement as to the management of the pump weaning parameters or pharmacological therapies. The variability in success of recovery has not only made it difficult to propose a protocol for treatment but has also limited the way these patients are followed. Assessment of recovery has been attempted using echocardiographic measurements, hemodynamic parameters, exercise and stress testing in various settings and combinations thereof [52]. Perhaps the most well-known and most commonly referenced study of LVAD support as a BTR is the Harefield Recovery Protocol study, where specific mechanical and medical therapies were outlined, resulting in a 75% recovery rate in the 15 nonischemic patients [46]. This will continue to be a difficult area to standardize given the continuous advances in mechanical devices and various pharmacological therapies and combinations thereof and will take a well-designed trial to elucidate further. One particular trial attempting this feat is the RESTAGE trial, which is currently enrolling participants to evaluate the 18-month recovery of patients with HMII LVADs in conjunction with a four-drug HF regimen [54]. Furthermore, other areas of interest in combination therapy include the use of stem cell therapy with LVADs to improve RR of the cardiomyocyte. Mesenchymal progenitor cells have shown significant promise in their ability to expand in culture and differentiate into functional cardiomyocytes. The data have been proven in vitro and in vivo translational experiments and have now progressed into clinical trials [55]. There is currently a NIH-sponsored multicenter double-blinded randomized controlled trial evaluating the use of allogeneic mesenchymal precursor cells in conjunction with a HMII LVAD in myocardial recovery. Better selection

One of the more difficult problems in treating patients with BTR is the appropriate selection of candidates. To this point, there are no standardized criteria for selection. Optimum candidates have been described in various individual studies, but the variation is not insignificant [31]. Traditional LVAD candidates have been those who fall in INTERMACS class 2–3 (i.e., those who are inotrope-dependent). In recent years, there has been interest in the use of LVAD therapy for potential recovery of patients in a more stable INTERMACS 5–7 category [46]. The REVIVE-IT trial has recently opened patient recruitment 595

596

Retrospective

Retrospective

Retrospective

Retrospective

Prospective

Prospective

Retrospective

Retrospective

Retrospective

Prospective

Prospective

Prospective

Hetzer et al. (2001)

El-Banayosy et al. (2001)

Bruckner et al. (2001)

Farrar et al. (2002)

Khan et al. (2003)

Gorcsan et al. (2003)

Dandel et al. (2005)

Simon et al. (2005)

Matsumiya et al. (2005)

Birks et al. (2006)

George et al. (2006)

Liden et al. (2007)

HF: Heart failure; LVAD: Left ventricular assist devices. Adapted from [6,46,77].

Prospective

Retrospective

Ueno et al. (2000)

Birks et al. (2011)

Retrospective

Helman et al. (2000)

Retrospective

Retrospective

Sun et al. (1999)

Dandel et al. (2008)

Prospective

Mancini et al. (1998(b))

Retrospective

Retrospective

Mancini et al. (1998(a))

Klotz et al. (2007)

Prospective

Muller et al. (1997)

Prospective

Retrospective

Levin et al. (1996)

Maybaum et al. (2007)

Study type

Study (year)

35 19

19

56

37

18

2

15

11

74

131

11

12

249

13

13

95

–

2

51

12

51

17

1

NICM

188

104

67

18

7

15

11

154

131

18

16

271

18

13

95

1

2

111

18

111

17

1

Patients

–

–

40

30

–

5

–

–

80

–

5

4

–

5

–

–

–

–

60

6

60

–

–

ICM

Disease

–

–

8

–

–

–

–

–

–

–

2

–

22

–

–

1

–

–

–

–

–

MCD

71

66

–

7

15

154

–

16

13

90

1

2

111

1

Pulsatile

33

1

–

–

–

–

–

–

–

5

–

–

–

–

Nonpulsatile

LVAD type

40.9

18.7

29.0

19.0

28.0

23.0

46.0

64.7

14.0

32.0

33.4

33.0

8.1

23.0

7.7

20.0

3.0

24.0

14.3

14.3

13.0

32.9

26.0

Mean LVAD duration (weeks)

Table 1. This chart describes the success other studies have reported in left ventricular assist devices recovery.

63.2

18.6

4.8

9

16.7

0

73.3

45.5

6.5

24.4

33.3

56.3

81.1

22.2

–

29.5

100

100

4.5

5.5

4.5

29.4

100

Weaning rate (%)

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/20/15 For personal use only.

–

37.1

40

0

67

–

9

–

20

31

33

33

–

–

43

0

100

–

–

100

–

100

Recurrent HF (%)

[79]

[78]

[77]

[76]

[75]

[74]

[73]

[72]

[71]

[70]

[69]

[68]

[67]

[66]

[65]

[64]

[63]

[62]

[61]

[60]

[60]

[59]

[58]

Ref.

Review Halbreiner, Cruz, Starling et al.

Expert Rev. Cardiovasc. Ther. 12(5), (2014)

[83]

[84]

1.5

16.5

[25]

18 49

13.8 182 18

Over the past 10–15 years, LVAD technologies have rapidly expanded and advanced the field for treatment of end-stage HF. The devices today are smaller, more efficient and durable with fewer complications compared with the earlier PF pumps. Despite dramatic advances in the field of mechanical circulatory support, the relatively high short- and long-term cumulative morbidity of these devices has exposed the shortcoming of this technology in its current state. Unless dramatic advances in mechanical circulatory support occur that would significantly reduce complications, the holy grail of therapy for HF remains the ability to promote recovery of the native heart. In this respect, the multiple positive observations related to the geometric, physiological, biochemical and structural RR induced by LVADs have been promising and offer a significant opportunity for investigation. We anticipate that with ongoing prospective trials of recovery a better molecular understanding of RR will be forthcoming. In addition, further refinement of patient management with respect to fine-tuning of the LVAD speed to optimize unloading, with more active management of the LVAD speed during weaning over a longer duration, may be necessary to achieve better clinical results. Improved understanding of myocyte regeneration, with or without the use of adjunctive stem cell therapy, will hopefully pave the way for better clinical success in the use of LVADs as BTR.

Retrospective

Retrospective

Yagdi et al. (2012)

Nasir et al. (2012)

HF: Heart failure; LVAD: Left ventricular assist devices. Adapted from [6,46,77].

Retrospective Dandel et al. (2012)

66

Prospective Patel et al. (2013)

67

Retrospective Kyobu et al. (2013)

384

66

13

–

8

–

32

–

and aims to assess the clinical outcomes in patients in this ‘lesser sick’ group after implantation of a HMII device [56]. It is possible that success of ventricular recovery will be higher in the ‘lesser sick’ patient population. Although this is not a trial aimed at assessing recovery, close follow-up of these patients may shed a light on this issue. In general, ideal candidates are those with nonischemic cardiomyopathy, even though some studies have suggested that patients with ischemic HF can benefit [57]. Also, the selection of the device as well as mode of operation has not been studied well enough. There is still no agreement about the optimal device for recovery (newer generation CF devices versus PF devices) as well as the appropriate weaning and unloading, as described earlier [46].

37.7

[82]

14.3 117 21 21

0

[81]

– – 5.0 20

0 23.5 30.4 17 – 2 1 1 Retrospective Lamarche et al. (2011)

17

NICM

ICM

MCD

Pulsatile

Nonpulsatile

Weaning rate (%) Mean LVAD duration (weeks) LVAD type Disease Patients Study type

informahealthcare.com

Review

Expert commentary

Study (year)

Table 1. This chart describes the success other studies have reported in left ventricular assist devices recovery (cont.).

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/20/15 For personal use only.

Recurrent HF (%)

[80]

Ref.

Myocardial recovery

Five-year view

The field of mechanical circulatory support in terms of LVAD technology will continue to advance over the next 5 years. More biocompatible devices with better flow and more physiologically responsive pump algorithms that will allow pulsatility will likely become available. Concomitant with development of totally implantable LVADs with transcutaneous energy delivery systems, the therapy will become more socially acceptable. It is anticipated that if these advances lead to meaningful improved outcomes, beyond just survival as the yardstick of success, then the technology will expand into patients with earlier stage HF. The field of mechanical circulatory support will only advance if morbidities related to gastrointestinal bleeding, infections, strokes and pump thrombosis are minimized. Application of 597

Review

Halbreiner, Cruz, Starling et al.

LVAD therapy in patients who are in earlier stages of HF, in whom the ventricle is not terminally remodeled, may significantly increase the success of myocardial recovery. Financial & competing interests disclosure

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/20/15 For personal use only.

This work was supported in part by Health Resources and Services Administration contract 234-2005-37011C. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of

the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • Heart failure continues to be one of the most prevalent diseases, and effective treatment continues to be a difficult task. • The potential for myocardial cells to reverse remodel is an intricate process involving multiple effects at mechanical, cellular and genetic levels. • Left ventricular assist devices (LVADs) are evolving and improving and will undoubtedly continue to have a positive impact on ventricular unloading and reverse remodeling. • Current literature continues to show promise in LVAD therapy as a method to allow bridge to recovery. • To achieve adequate recovery will entail not only the use of LVADs alone, but in conjunction with other therapies, including pharmacologic as well as newly studied stem cell therapies. • In order for a large randomized trial to evaluate the true effect of LVAD on recovery, there needs to be a standardization of the treatment regimen and weaning protocols. The ongoing RESTAGE trial has potential to do this. • There are limitations to the implementation of LVADs in recovery including a defined protocol, follow-up methods and determination of length of therapy and the appropriate patient selection.

theme: age. J Heart Lung Transplant 2013; 32(10):951-64

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