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Review Article

LVAD-Induced Reverse Remodeling: Basic and ClinicalImplications for Myocardial Recovery

DANIEL BURKHOFF, MD, PhD, 1 ,2 ,3 STEFAN KLOTZ, MD, 4 AND DONNA M. MANCINI, MD 2

Orangeburg, New York; New York, New York; Muenster, Germany

ABSTRACT

Background: With improved technology, increasing clinical experience, and expanding indications for

use, left ventricular assist devices (LVADs) are assuming a greater role in the care of patients withend-stage heart failure. Early in the course of LVAD use as a bridge to transplant, it became evidentthat some patients exhibit substantial recovery of ventricular function, which led to the concept of reverseremodeling.Methods and Results: Herein we summarize and integrate insights derived from a multitude of studiesthat have investigated how LVAD support inuences ventricular structural, cellular, extracellular matrix,molecular, biochemical, and metabolic characteristics of the end-stage failing heart. The focus includesa review of the extent and sustainability of reverse remodeling, the important advances in understandingof the pathophysiology of heart failure derived from these studies and the implications of these ndings fordevelopment of new therapeutic strategies.Conclusion: In brief, studies of LVAD-heart interactions have led to the understanding that although weonce considered the end-stage failing heart of patients near death to be irreversibly diseased, when givensufcient mechanical unloading and restoration of more normal neurohormonal milieu, a relatively largedegree of myocardial recovery is possible. Comparison of effects on right and left ventricles have provided

mechanistic insights by implicating hemodynamic unloading as primarily regulating certain aspects of reverse remodeling, neurohormonal factors as regulating other aspects, and joint regulation of still otheraspects. As such these observations have driven a shift of thinking of chronic heart failure as a progressiveirreversible disease process to a potentially treatable entity.Key Words: Heart failure, extracellular matrix, hypertrophy, right ventricle, excitation-contractioncoupling.

With improved technology, increasing clinical experi-ence, and expanding indications for use, left ventricular as-sist devices (LVADs) are assuming a gr eater role in the care

of patients with end-stage heart failure.1

Early in the course

of LVAD use as a bridge to transplant, it became evidentthat some patients exhibit substantial recovery of ventricu-lar function. This prompted explantation of some devices in

lieu of transplantation, so called bridge-to-recovery (BTR)therapy. 210 So far, outcomes following these early experi-ences have been poor. Many patients treated in this fashionhave progressed rapidly back to heart failure or have died of heart failurerelated complications. Therefore, LVADs arenot generally used with the intention of bridging patientsto recovery. However, knowledge has emerged from studiesof hearts supported by LVADs that provides insights intothe basic mechanisms of ventricula r remodeling and possi-ble limits of ventricular recovery. 1115 In general, it wasthese studies that spawned the concept of reverse remodel-ing,16 now recognized as an important goal of many heartfailure treatments. Indeed, the effect of LVAD support is

From 1 J. Skirball Center for Cardiovascular Research, Cardiovascular Research Foundation and 3 IMPULSE Dynamics, Orangeburg, NY; 2 Division of Cardiology, Columbia University, New York, New York; 4 Department of Thoracic and Cardiovascular Surgery, University Hospital, Muenster, Muenster, Germany.

Manuscript received June 13, 2005; revised manuscript receivedOctober 9, 2005; revised manuscript accepted October 18, 2005.

Reprint requests: Daniel Burkhoff, MD, PhD, The Jack H. Skirball Cen-ter for Cardiovascular Research, Cardiovascular Research Foundation, 8Corporate Dr, Orangeburg, NY 10962.

1071-9164/$ - see front matter 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.cardfail.2005.10.012

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Table 1. Summary of Prior Research on the Impact of LVAD Support on Ventricular and Myocardial Properties *

Feature Summary of Findings References

Hemodynamics Improved blood pressure, cardiac output, and pulmonary venous pressure ManyIncreased central venous pressure/right heart failure 1722

Normalized pulmonary vascular resistance 17,23

Normalized plasma volume 24

Improved LV contractility measured by E es (case report) 25

Improved end organ function (eg, renal, liver) 26

Heart structure and function LV chamber size decreases 16,18,27,28

LV mass decreased 16,27,29,30

LVAD inow regurgitation prevents reverse remodeling 31

LA size decreased 5,32

Decreased mitral regurgitation 33

Improved mitral lling (normalized E/A) 34

RV chamber does not decrease in size 18

Cell size Regression of LV myocyte hypertrophy 18,27,29,30,32,3541

RV myocytes do not show regression of hypertrophy 18

Myocardial function Basal force of contraction improved 18,4244

Force frequency relationship improved 18,42,43,45

b -adrenergic responsiveness improved (LV and RV) 19,42,44

Calcium cycling SERCA-2a expression improved in LV, not RV 18,27,43,46

Increased sarcoplasmic reticular calcium pumping function 39,43

Na 1 -Ca2 1 exchanger expression and function improved 43,45

Ryanodine receptor function improved (LV and RV) 19,47

L-type calcium channel and transsarcolemmal calcium ux improved 39,48

Overall improvement of calcium cycling 39

Adrenergic pathway Improved b -receptor density in LV and RV 19,44,47,49

Improved a -receptor density 50Caveolin expression increased 51

Neurohormones (all decreased) Epinep hrine and norepinephrine 52,53

Angiotensin II 52

Aldosterone, rennin, arginine vasopressin 24

ANP 24,29,51,52,5456

BNP 29,54,57,58

ET-1 58

Cytokines (decreased except as otherwise noted) IL-1 59,60

IL-6 (increased further by LVAD; unknown signicance) 5962

IL-8 61

Tumor necrosis factor- a 41,55,59,6366

Complement C3a 61

Sarcomeric and cytoskeletal proteins Dystroph in improved in LV and RV 6769

Improved sarcomeric proteins in LV and RV 70,71

partial improved sarcomeric proteins 38,72

Extracellular Matrix LV collagen increased 27,32,34,73

LV collagen decreased 36,74

RV collagen increased 65

RV collagen unchanged 20

MMPs downregulated 73,75

TIMPs upregulated 73,75

Increased myocardial mast cells than inuence extracellular matrix 76,77

Metabolism Increased mitochondrial respiration rate 78,79

Reduced metallothionein (improved oxygenation) 35

Partial recovery of downregulated metabolic genes 56

Creatine kinase increased toward normal 80

Reduced hypoxia-inducible hemeoxygenase-I (improved oxygenation) 81

Reduced oxygen consumption 82

Cardiolipin improved in ICM, not DCM 83

Signaling and Apoptosis Decreased apoptosis 37,8489

Increased apoptosis 90,91

Bcl-2 normalized 84

Receptor Tyrosine Kinase (RTK) 55,92

PKB/Akt/GSK-3 b pathway increased or no change 87,93

MEK/Erks pathway decreased 87,94

NF-kappaB decreased 95

MAP-Kinase, p44/42, p38 kinase, c-Jun, JNK1/2 37

iNOS expression 89

IGF-1 96

Miscellaneous QTc and shortened AP duration 97,98

Improved coronary ow reserve 99

Autonomic function improved 100

Use of gene arrays Normalized expressions of some, but not most abnormally expressed genes 72,96,101103

Focus on TIMPs and MMPs 75

Focus on GATA-4 104

Focus on genes associated with vascular organization 94,104

Clinical recovery LVAD assessed as bridge to recovery in chronic heart failure 13,105110

LVAD used as bridge to recovery in acute heart failure 5,111114

Use of clenbuterol to enhance recovery 96,108,115,116

Stress test used to identify LV recovery during partial LVAD support 3,40

LVAD, left ventricular assist device; LV, le ft ventricle; RV, right ventricle; ANP, atrial naturetic protein; BNP, brain naturetic protein; ET-1, endothelin-1; IL,interleukin; MMP, matrix metalloproteinases; TIMP, tissue inhibitors of metalloproteinases; iNOS, inducible nitric oxide synthase.

*To limit the number of citations, some references have necessarily been excluded from this listing.

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profound, impacting on nearly every aspect of myocardialand systemic properties that is pathologically altered inthe heart failure state; a detailed overview of studies per-formed to date is provided in Table 1 . For the sake of brev-ity it is not possible to discuss all aspects detailed in thistable nor possible to include every reference published onthis rapidly growing eld. This review attempts to summa-

rize and integrate insights derived from these studies asthey pertain to advancing understanding of the pathophysi-ology of heart failure, the extent and sustainability of reverse remodeling, and to their implications for develop-ment of new therapeutic strategies.

Primary and Secondary Effects of LVAD Support

LVADs were designed primarily to assume responsibilityfor pumping blood to restore normal cardiac output andblood pressure ( Figs. 1 and 2) and allow reduction (or elim-ination) of the need for toxic levels of pressor and inotropicsupport. 4,23,25,26 With LVADs of most designs, this isachieved by withdrawing blood from the left ventricle oratrium and returning it to the arterial system.

In addition, there are at least 2 benecial secondaryeffects of LVAD support. First, based on their anatomicconnections, LVADs are pumps functionally positioned inparallel to the normal left ventricle. As such, they divertblood from the left ventricle and provide profound LV pres-sure and volume unloading. This also results in reductionsin pulmonary venous and arterial pressures and reducedpulmonary vascular resistance (ie, right ventricular afterloadis reduced). 17,23 Second, by normalizing blood pressure andcardiac output, LVAD support improves perfusion to allbody organs, which results in improved autonomic func-tion100 and normalization of the neurohormonal and cyto-kine milieu that is present in heart failure. The potentialsignicance of these secondary effects may have been unan-ticipated by early LVAD designers, but their profoundimportance is now widely recognized. Heart failure is con-sidered a systemic disease that affects many organs becauseof hypoperfusion and the abnormal neurohormonal andcytokine milieu; normalization of this milieu by LVADspromotes systemwide recovery.

Not all secondary effects of LVAD support, however, arebenecial. LVADs provide pressure and volume unloading

only to the LV. In the face of increased cardiac output,the right ventricle (RV) is often volume overloaded and un-able to accommodate the resultant ow. 1722 Consequently,right heart failure (ie, normal or low cardiac output, normalor low pulmonary venous pressure with high central venouspressure) and RV distenti on occur in as many as 20% to30% of LVAD recipients. 21,22 In many instances this canbe treated with inotropic agents or pulmonary vasodilators,but in some instances simultaneous right ventricular sup-port is required.

As detailed later in this article, investigators have takenadvantage of these differential effects on the LV and RVto clarify mechanisms of remodeling and reverse

remodeling. Although the neurohormonal milieu is deter-mined largely (though not entirely) by the blood perfusing

the myocardium and is therefore common to the left ventri-cle and RV, hemodynamic benets of LVADs are provided,for the most part, only to the left ventricle. Consequently,comparisons of effects on the right and left ventricles al-lowed identication of whether primary mechanism of spe-cic aspects of recovery are due to hemodynamic factors, toneurohormonal factors, or to both.

Ventricular Structural Reverse Remodeling

Ventricular structure is characterized by LV musclemass and the end-diastolic pressure-volume relationship

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Fig. 1. Acute hemodynamic effects of left ventricular assist device(LVAD) support schematized in pressure-volume loops (top) andtime plots of ventricular pressure, aortic pressure, and ventricularvolume (bottom). Before LVAD, end-diastolic pressure and vol-ume are high, whereas aortic pressure is low. When an LVADpumping in synchrony with the native heart beat (with a pulsatilepump such as the HeartMate) is turned on, end-diastolic pressureand volume drop dramatically, and cardiac output is derived exclu-

sively from the LVAD. Peak ventricular systolic pressure also fallsdramatically, aortic pressure rises dramatically and the aorticvalve does not open. Ventricular contractions serve primarily asa booster pump to ll the LVAD. Acutely, ventricular end-systolicpressures and volumes fall on the original end-systolic and end-diastolic pressure-volume relations (ESPVR and EDPVR, respec-tively) shown by gray dotted gray lines in top panel; over time, theheart reverse remodels and these curves shift leftward towardmore norm al, smaller volumes. Curves obtained from a computersimulation 141 modied to include a pulsatile LVAD.

LVAD-Induced Reverse Remodeling Burkhoff et al 229


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(EDPVR). 117 Although studied for decades previously, itwas not until the seminal work of Pfeffer and colleaguesthat it was demonstrated in experimental heart failure thatthis relationship shifts rightwards toward larger volumesin chronic heart failure, a phenomenon they called ventric-ular remodeling. 118 It is known that such structural ventric-ular remodeling results from changes in cell width and

length (hypertrophy), ber rearrangement, and extracellularmatrix changes in response to the abnormal stresses andneurohormonal stimulation present in heart failure. Similarshifts of the EDPVR in human heart failure were soon con-rme d in both ischemic and idiopathic cardiomyopa-thies. 119,120 Interventional studies in animals and humanssuggested that the extent of remodeling could be limited,at least afte r acute myocardial infarction, with the use of vasodilators. 121 However, in the 1980s and early 1990s, itwas generally believed that after the heart was markedly di-lated, no form of therapy could meaningfully reverse thatprocess, which led to the generally held concept of irrevers-ible, end-stage cardiomyopathy.

Among the initial case reports of patients undergoingprolonged LVAD support, a chest X-ray published by Fraz-ier4,122 showed a small cardiac silhouette after prolongedLVAD support suggesting, in contrast to the preoperativesevere chamber dilation, the presence of a nondilated heart.It was recognized that this nding could simply have beendue to the unloading provided by the pumping LVAD,

which decompressed t he would-be dilated heart, particular-ly in the acute setting. 32,34 However, this was subsequentlyshown not to be the case a fter chronic support through ex-amination of the EDPVRs. 16 LV EDPVRs were measuredfrom human hearts explanted at the time of orthotopictransplantation in patients requiring LVAD support, fromthose not requiring LVAD support, and from several normalhuman hearts not suitable for transplant ( Fig. 3A). Com-pared with normals, EDPVRs of nonLVAD-supportedhearts were shifted toward markedly increased volumes (re-modeling). In contrast, EDPVRs from LVAD-supported

Fig. 2. Parasternal long axis echocardiograms taken from a patientabout 1 week after implantation of a pneumatic left ventricular as-sist device (LVAD) during a venting cycle when the LVAD istemporarily off (A) and minutes after the device is turned back

on (B). Withthe device off, theLV is dilated. Withthe deviceturnedon, the LV size decreases markedly (volume unloading), althoughthe RV remains loaded. LV, left ventricle; RV, right ventric le; IC,LVAD inow conduit; Ao, aorta. Adapted from Levin et al. 16

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Fig. 3. The ventricular end-diastolic pressure-volume relation(EDPVR), initially shifted far rightward in heart failure, shifts,over time, back toward normal. Shown in (A) are averageEDPVRs from normal human hearts, from failing hearts not sup-

ported with LVAD, hearts supported with an LVAD for less than40 days and hearts supported with in LVAD for more than 40days. (B) Heart size, indexed by V30, the volume required toachieve an end-diastolic pressure of 30 mm Hg as a function of duration of LVAD support from individual hearts (see a insertfor symbol key). Also shown are values from normals and fromfailing hearts not supported by LVAD. Underlying the reductionin heart size is regression of cellular hypertrophy. (C) Cross-sectionof normal human myocardium. In chronic heart failure (D), themyocytes are markedly hypertrophic. After LVAD support (E),LV myocardial hypertrophy regresses (individual myocyte cross-sectional area reduced). Increased interstitial brosis is also noted.All myocardial samples used for C E were xed in an unloadedstate. All gures from Madigen et al. 27



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hearts were more similar to normal. The near-normal posi-tion of these EDPVRs reected a shift of the relations fromhigh to signicantly lower volume. We referred to this sh iftof the EDPVR back toward normal as reverse remodeling. 16

The time course of reverse structural remodeling has beeninferred by plotting the position of the EDPVR (indexed bythe volumeat a xedpressu re of30mmHg,V 30 )asafunction

of LVAD support ( Fig.3B).27

This relationassumeda roughlyexponential time course with average time constant of 30.8days, with the process reaching its maximal effect by about90 days. On average, however, the hearts did not return tocompletely normal size. V 30 averaged about 280 mL withoutLVAD support, about 150 mL after maximal reverse remod-eling compared with about 100 mL in the normal hearts.

The right ventricle of the failing heart is also generallydilated, though not as signicantly as the LV. RV V 30 isabout 80 mL in normal hearts and reaches about 150 mLin cardiomyopathy. 18 In contrast, RV V 30 of LVAD support-ed hearts also averages about 150 mL, indicating that thestructural rev erse remodeling is not generally observed inthis chamber. 18 Because central venous pressures remainselevated during LVAD support, 1722 the lack of reversestructural remodeling in the RV at the same time when re-verse structural remodeling is strongly present in the LVsignies that reverse structural remodeling is primarily me-diated the hemodynamic unloading and not by normalizedneurohor monal milieu. Because LVADs also reduce RVafterload, 17,23 the factor regulating reverse structuralremodeling can even more specically be targeted as the re-duction in preload. Additional support for this hypothesis isprovided by the ndings that (1) on the rare occasion whenan LVAD inow valve failed the heart would be reloadedand would redilate (rightward shifted EDPVR) despitemainten ance of normal forward cardiac output and bloodpressure 31 and (2) that indeed RV V 30 regresses toward nor-mal in hearts of patients receiving right ventricular devicesupport. 123 Similar univentricular effects are observed onregression of free wall mass and cellular hypertrophy(Fig. 3C3E).18,27,29,30,32,3539 The time course of changeof LV m yocyte cell dimension paralleled changes in ma ssand V30 ,

27 but no such changes were observed in the RV. 18

Finally, in addition to normalized myocyte diameter,LVAD support induces normalization of the cytoskeletonas evidenced by normalizatio n o f sarcomeric proteins,

vinculin, desmin, and b-tubulin.38,6771

Improved Myocardial Function

In addition to the effects on structure, studies of trabeculaeand myocytes isolated from LVAD supported hearts alsodemonstrate improved intrinsic myocardial contractile prop-erties. Dipla et al rst described that LVAD support led to in-creased contractile strength, faster time to peak contraction,and reduced time to 50% relaxation in isolated cardiomyo-cytes. 42 It was demonstrated in this same study that myo-cytes also exhibited improved contractile responses toincreased frequency of stimulation (normalized force-

frequency relationship, FFR) and to b-adrenergic stimula-tion. These ndings were subsequently conrmed in isolatedtrabeculae. 18,19,4345 Recovery of the FFR correlated withimproved expression of calcium cycling genes and improvedcalcium accu mulating efcacy of the sarcoplasmic reticu-lum. 18,27,43,46 Improved b -adrenergic responsiveness corre-lated with improved b-receptor density and normalized

phosphorylation of the calcium release channel.19,44,47

Inter-estingly, we observed that the FFR improved in LV myocar-dium but not in RV myocardium, which also correlated withchamber-specic nor malized expression of genes involvedwith calciumcycling. 18 In contrast, b -adrenergic responsive-ness improved in myocardium of both RV and LV. Thesendings suggested that some aspects of functional recovery(eg, FFR and gene expression of calcium handling genes) areprimarily regulated by hemodynamic factors, whereas otherfactors (eg, b -adrenergic signaling) are primarily regulatedby normalized neurohormonal milieu.

Extracellular Matrix

In addition to structural and functional changes, LVADsupport is also associated with changes in the characteris-tics and metabolism of the extracellular matrix. In contrastto other aspects, however, extracellular matrix properties donot change uniformly in a manner indicative of conversionback to the normal state. Indeed, several studies show thatmyocardial collagen content increases during mechanicalunloading above the alre ady abno rmal levels observed inthe chronic failing state. 27,32,34,73 In contrast, results of a few studies indicated the opposite. 36,74 In our recent studywe showed that LVAD support was associated with a signif-icant increase in total and es pecially crosslinked collagendeposition in LV myocardium. 20 MMP-1 and MMP-9 levelsand activity (matrix metalloproteinases, which are enzymesinvolved in breakdown of collagen), which are increased inthe failing state, tended to decrease following LVAD sup-port. Concomitantly, TIMP-1 (tissue inhibitors of metallo-proteinases) levels increased tremendously after LVADsupport, leading to a normalization of the MMP-1/TIMP-1 ratio. In addition, myocardial tissue levels of angiotensinI and II, known regulators of myocardial collagen synthesis,increased during LV unloading and the ratio of type I totype III collagen shifted (abnormally) to the more stiff

type I collagen. In aggregate, these ndings suggestedthat the high rate of collagen breakdown observed in end-stage heart failure is reduced during LVAD support, result-ing in an overall increase in collagen content. We also ob-served that these biochemical changes lead to an increase inmyocardial stiffness, which we speculated could be a factorcontributing to the only rare occurrence of full recovery of function after LVAD support and the often progressive de-terioration of pump function after LVAD explantation (aswill be discussed later in this article). Findings in the RVwere somewhat mixed, with most aspects trending in thesame direction as in the LV, but typically not reaching sta-tistical signicance. This somewhat ambiguous picture lead



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us to conclude that both neurohormonal and mechanicalfactors likely contribute importantly to extracellular matrixmetabolism.

Molecular, Biochemical, and Metabolic Changes

As alluded to previously, the structural and functional

improvements in myocytes and ventricular chamber haveas their basis normalized expression of certain genes andposttranslational regulation of certain proteins that improvecellular functions and metabolism. It is well known thata multitude of changes in myocardial gene expression occurin heart failure that are generally considered to reect a shiftfrom the normal adult to a fetal gene program. 124 Teliolog-ically, this shift is believed to be driven by the mechanicaland neurohormonal stresses of heart failure, features of which partially mimic the fetal environment. Comparedwith adult myocytes, fetal myocytes have a greater abilityto undergo cell division. The changes associated with heartfailure can thus be viewed as a response that reverts thegenotype to a state in which the cells were more readilyable to increase cell number and normalize wall stress.Because the transformation to the fetal state is incomplete,the mechanical and neurohormonal environment driveshypert rophy and, ultimately, apoptosis (programmed celldeath). 125,126

The inuence of LVAD support on gene expression, pro-tein content, and protein function has been studied by severalgroups. As discussed previously, early studies showed nor-malization of expression and function in the LV (not theRV) of proteins involved with calcium handling known tobe abnormal and contribute to contractile dysfunction in heartfailure. Many studies have also focused on expression of genes involved with hypertrophy, cell cycling, and apoptosis.A majority of studies suggest that these genes shift towardnormal during LVAD support and indicate a regression of hy-pertrophy and reduction in the amount of apoptosis ( Table 1 ).However, not all such genes are normalized by LVAD sup-port. Razegi et al showed that the PKB/Akt/GSK-3betapathway is not activated during LVAD support and concludedthat other signaling pathways must be responsible for theimprovement of cellular function and cell survival. 93

Studies of the inuence of LVAD support on myocardialmetabolism have also yielded mixed results. On the one

hand, improvement of overall myocardial mitochondrialf unction, 78,83 normalized expression of uncoupling protein356 and enhanced caveolin expression (hypothesized to con-tribute to improved lipid metabolism) 51 have been reported.On the other hand, gene expression of other proteins in-volved in metabolism that are downregulated in heart fail-ure (eg, glucose transporter 1 and 4 and muscle carnitinepalmityl transf erase-1) are not normalized during mechan-ical unloading. 56 Thus it appears that LVAD support onlypartially reverses depressed expression of genes involvedin metabolism in the failing human heart.

More recently, microarray GeneChip platforms havebeen used to survey changes in transcription patters in

response to LVAD support. 103 Hall et al showed that 22genes were downregulated , whereas 85 genes were upregu-lated after LVAD support. 104 Genes involved in regulationof myocardial hypertrophy and vascular signaling were sig-nicantly downregulated. Using this technique, our groupshowed that calcium-handling genes were upregulated,whereas genes involved with regulation of my ocardial -

brosis did not change on the transcription level.102

Margu-lies et al identied 3088 transcripts that exhibited abnormalabundance. As a consequence of LVAD support, only 11%of these genes exhi bit partial recovery and only 5% showedtrue normalization. 101 This latter study in particular rein-forced the notion that although normalization of specicgenes of interest can be identied after LVAD support,the normalization is not ubiquitous and expression of many genes (in fact a vast majority of genes), is still abnor-mal and may provide clues as to why function is not com-pletely normalized in most LVAD patients. In the mostrecent study, Birks et al used microarray technology to as-sess gene expression proles in LVAD patients who recov-ered to a degree that permitted LVAD explant c omparedwith those in which recovery was insufcient. 72 Theseinvestigators found distinct differences in expression of sarcomeric and cytoskeletal proteins between the 2 groups,which led to interesting new hypotheses about the mecha-nisms of recovery. Still, studies of protein content and pro-tein function lag behind studies of gene expression inidentifying the number of proteins that are either presentin abnormal quantities or whose function is abnormal.

Mechanisms of Reverse RemodelingAre Unknown

The biology of how cardiac muscle responds to altera-tions in mechanical stress remains largely unknown. Mostprior research has been devoted to understanding the impactof increased afterload as occurs in myocardial hypertrophy.Yet, after more than 40 years of physiologic, biochemical,and molecular research, it is still not fully understoodhow stress or strain regulate gene expression, assembly of sarcomeric and cytoskeletal proteins, and modify calciumcycling and function of other ion channels. Membranebound macromolecules that link extracellular matrix andintracellular elements (integrins) and membrane bound

components of a multitude of signaling cascades (eg, path-ways involved in a - and b-adrenergic signaling, growthhormones, phosphokinases) have all been implicated inthe hypertrophic response through their impact on manysignaling cascades. Less well studied is the response of the normal heart to mechanical unloading and the develop-ment of atrophy. It has been our simplistic assumption thatthe mechanisms leading to normalization of myocardial ab-normalities present in heart failure during mechanical un-loading by LVADs reects normalization of these verysame signaling cascades invoked during hypertrophy as op-posed to recruitment of pathways specic for the generationof atrophy. Although evidence available thus far is



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consistent with our assumption, this is an assumption thathas yet to be tested. So far, tissue derived from patients un-dergoing LVAD support provides the best opportunity tostudy this because of the paucity of experimental modelsof myocardial unloading or reverse remodeling.

Effects of Different LVAD Flow Patternson Reverse Remodeling

In general, 2 different classes of LVADs are now in us efor long-term support: pulsatile and non-pulsatile LVADs. 9

During the last decade, pulsatile LVADs were dominant inclinical use, but nonpulsatile devices are now the dominantform in development as next-generation applications. Stud-ies are beginning to compare the physiologic effects of pul-satile and nonpulsatile LVADs. For example, Loebe et alshow that the inammatory response measured by tumornecrosis factor- a and C5a was signicantly more increasedafter implant ation of a nonpulsatile LVAD than with a pul-

satile LVAD.66

Potapov et al showed that biochemicalmarker of brain damage were similar between the 2LVAD types in the rst 14 days after implantation, 127 sim-ilar to the study from Vatta et al, who demonstrated reversalof disruption o f dystrophin with either pulsatile or nonpul-satile LVADs. 69 Only 1 study evaluated hemodynamiceffects during long-term support with nonpulsatile and pul-satile LVADs. 23 It was found that LV pressure unloadingwas similar between these 2 types of LVADs, whereas LVvolume unloading was signicantly more pronouncedwith a pulsatile device. Most recently, Thohan et al showedthat although there are differences between these 2 classes

of devices with regard in magnitude of unloading, bothforms of support were equally effective in normalizingcell size and tumor necrosis factor- a levels.41 These ndingmight provide important insights into the remodelingprocess with different LVAD support. 128

Clinical Evidence of LVAD-Induced VentricularContractile Recovery

Although recovery of LV function is commonly observedwhen LVA Ds are used in the setting of acute heart failuresyndromes, 5,111114 the concept of recovery of ventricular

function in patients with chronic heart failure after LVADhas been described only recently. It is noteworthy, however,that all of the research described concerning the relativelylarge degree of structural and functional reverse remodelingin chronic heart failure was entirely spawned by early clin-ical observations that signicant recovery of LV functionoccurs during LVAD support.

The rst reported case of cardiac functional recovery af-ter LVAD support involved an otherw ise healthy young manwith an idiopathic cardiomyopathy. 2 At the time of in-tended transplant, the native heart was observed to havenormal hemodynamic measurements with a normal ejectionfraction. The transplant was aborted, the LVAD explanted

and the patient became the rst BTR with a HeartMateLVAD. After LVAD removal, however, the heart progres-sively redilated to its original pre-LVAD condition andunfortunately the patient succumbed to heart failure. Theinitial elation of investigators was dashed by the realizationthat the recovery could not be sustained when the heart wasre-exposed to the hemodynamic load of the circulation.

Since our rst experience, several groups have reportedtheir clinical experiences conce rning recovery of ventricu-lar function post LVAD support. 129 The results have varied,with some centers reporting a high frequency of LVADexplantation followed by sustained recovery and othersonly describing rare cases of myocardial recovery.

Based on a retrospective chart review, we observed only5 patients from among 111 patients with chronic heart fail-ure who exhibited sufcient recovery to permit LVAD ex-plantation without transplantation. 3 All of these patientseventually developed recurrent heart failure, with 2 patientsrequiring a second LVAD for recurrent heart failure and theremaining 3 patients dying of progressive heart failure.

We also used exercise stress testing (including exercisehemodynamics, echocardiography, and oxygen consump-tion), to identify potentially recovered patients. 3 Patientsunderwent cardiopulmonary exercise testing with theLVAD providing full support. Exercise was repeated inthose patients who were able to tolerate weaning of owto about 2 L/minute. Patients were considered for deviceexplantation if they were able to exercise with minimalLVAD support and achieve a maximal oxygen consumptionof 20 mL$kg$minute or peak cardiac output greater than10 L/minute. Thirty-nine patients underwent cardiopul-monary stress testing approximately 3 months after LVADimplant according to this strategy. Weaning to partial sup-port was achieved in only 7 of the 39 patients. Peak oxygenconsumption declined in these 7 patients from an average of 17.3 mL O 2$kg$minute during full support to 13.0 mLO2$kg$minute during partial support. The LVAD was ex-planted in only 1 patient demonstrating partial recoverydue to device infection. This patient subsequently requiredreinsertion of another LVAD.

Another strategy for identifying potential responders hasbeen through the use of dobutamine stress echocardiogra-phy. Preliminary data suggest that this technique may iden-tify patients with sufcient recovery to tolerate device

explantation.40

Kahn el al identied 9 of 16 patients withdilated cardiomyopathy in whom cardiac output increasedand pulmonary capillary wedge pressure maintained below15 mmHg in respons e to dobutamine; these 9 patients weresuccessfully weaned. 40 Six of these patients survived for atleast 1 year, but all subsequently died or required transplant(Torre, personal communication).

El Banayosy et al observed that only 1 of 13 LVADpatients could be successfully weaned, in whom hemo dy-namic measurements improved during LVAD support. 106

Helman et al described recurrent remodeling in two patients2 and 6 month after primary successful LVAD expl antationwith the need for recurrent LVAD implantation. 105 The



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mechanical circulatory support device database from 2004showed that LVADs were used as bridge-to-transplant in75.5% of cases, as destination therapy in 8.4% of casesand as BTR in 5.8% of cases. 1 Of the 24 patients fromthe BTR group, 7 died before transplant, 2 did not recoverafter LVAD placement and had to be transplanted, and inonly 8 patients LVAD explantation could be performed. Un-

fortunately, criteria used to select patients for BRT and fol-low-up reporting on freedom of recurrent heart failure afterdevice explant are not described and may not be uniform atthe different participating centers.

In contrast to these reports, the Berlin Heart Groupreports a higher frequency of LVAD-induced myocardialrecovery in patients with chronic idiopathic cardiomyo-pathy. 107 More than 33% of their patients with dilated car-diomyopathy have undergone device explantation forrecovery. Over a 10-year period, 33 patients with chronicnonischemic cardiomyopathy supported with an LVAD un-derwent explanation after recovery. The majority of thesepatients have sustained improvement with a 5-year survivalof 85%. Recurrence of heart failure was observed in 32% of patients by 2 years after device explantation. Six patientsrequired cardiac transplantation. One patient died of heartfailure and 3 patients died of non-cardiac causes after de-vice explantation. Predictors of sustained recovery includedLV end-diastolic dimension less than 55 mm and ejectionfraction greater than 45% during a 15-minute pump stop ex-periment and a less than 5 years history of heart failure(positive predictive value of stable heart function O 3 yearspost explant of 92%). Hetzer et al also observed that opti-mal improvement in LV size and function occurred withinapproximately 90 days of LVAD implantation, but n oteda gradual deterioration with longer periods of support. 130

The LVAD Working Group Recovery Study, a multicenterstudy including the 8 largest LVAD groups in the UnitedStates (Baylor, Cleveland Clinic, Columbia, Temple, TexasHeart Institute, and Universities of Michigan, Minnesota,Pittsburgh) was established in response to t hese contrastingreports of recovery during LVAD support. 109 In this pro-spective study, 67 LVAD patients underwent monthly as-sessment of cardiac function using echocardiography atfull and partial support. Fifty-ve percent of the patientshad dilated cardiomyopathy and 45% coronary artery dis-ease. Serial echocardiographic assessment obtained during

downtitrated LVAD support demonstrated signicant im-provement in LV ejection fraction and reduction in LV di-ameters as compared with pre-LVAD implantation. LVEFrose from an average of 17% preimplant to 34% at 1 monthafter implant during partial ventricular assist. Thirty-onepercent of patients had ejection fractions O 40%. Three pa-tients with acute heart failure (symptom duration ! 1 week)and 2 patients with recent onset CHF (duration ! 6 months)exhibited complete recovery and underwent successfulLVAD explant. One patient with chronic heart failure hadpartial recovery but underwent device explantation becauseof device malfunction. This patient quickly deterioratedwith ejection fraction falling from 35% to 20%.

Strategies to Enhance VentricularContractile Recovery

Another group reporting success in bridging cardiomyo-pathic patients t o full recovery and LVAD explant is theHareeld group. 108,115 Led by Sir Magdi Yacoub, thisgroup uses aggressive high dose heart failure medical ther-

apy early post device implant in combination with clenbu-terol, a b-2 adrenergic receptor agonist known in animalmodels to induce skeletal and car diac mus cle hypertrophyand improved contractile strength. 96,131133 Early after de-vice implant, patients are treated with angiotensin-convert-ing enzyme inhibitors, angiotensin receptor blockers,aldosterone antagonists, and b -blockers followed by initia-tion of clenbuterol. Of 15 patients managed at Hareeldwith this protocol, 70% (11 patients) demonstrated suf-cient recovery to allow device explantation. Clenbuterolwas stopped just before device explantation and not re-sumed. After 3 years of follow-up, the average reportedejection fraction of theses patients remains 60% to 65%.To date, only 1 patient is reported to have demonstratedclinical deterioration, and that was associated with signi-cant alcohol intake. More recently, this group found thatclenbuterol induces insuli n-like growth factor I (IGF-I) incardiac myocytes in vitro. 134 They subsequently examinedchanges in IGF-I expression in patients who recovered afterLVAD support combined with clenbuterol treatment. 96

They found that patients with low IGF-I mRNA levels atimplantation showed signicant increase during recoveryand those with high IGF-I mRNA at implantation remainedhigh. In both groups, levels returned to normal by 1 yearafter explantation. They concluded that elevated myocardialIGF-I mRNA levels could play a role in recovery by limit-ing atrophy and apoptosis during reverse remodeling.At this time a multicenter study is planned to determinewhether the results obtained at Hareeld can be replicatedby US centers (ie, Hareeld Recovery Protocol Study).

Conclusion

Shifts of ventricular and myocardial properties back to-ward normal observed during LVAD support are collectivelyreferred to as reverse remodeling. The term can be used in

a more focused manner by adding a qualier and specical-ly denoting structural, molecular, biochemical or metabolic,reverse remodeling. Although many properties exhibit pro-found reverse remodel during LVAD support (eg, ventricularmass and structure), this is not a ubiquitous process. Impor-tant examples of myocardial or ventricular properties thatdo not regress toward normal during LVAD support includeabnormal extracellular matrix metabolism, increased tissueangiotensin levels, myocardial stiffening, and partial recov-ery of genes involved with metabolism. Indeed, broad sur-veys of myocardial gene expression using gene chiptechnology reveal that expression of only a small percentageof abnormally expressed genes normalizes. 101



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In addition, LVAD support cannot correct an aquired orinherited gen etic defect that may underlie an idiopathic car-diomyopathy. 135 For the case of ischemic cardiomyopathy,LVAD support is not known to lead to repopulation of theinfracted tissue with contracting myocytes. These realitiesmay serve to establish theoretical and practical limits tothe extend and sustainability of LVAD-induced reverse

remodeling.Nevertheless, studies of LVAD-heart interactions have

led to the understanding that although we after consideredthe end-stage failing heart of patients near death to be irre-versibly diseased, when given sufcient mechanical un-loading and restoration of more normal neurohormonalmilieu, a relatively large degree of myocardial recovery ispossible. Comparisons of effects on right and left ventricleshave provided mechanistic insights by implicating hemody-namic unloading as primarily regulating certain aspects of reverse remodeling, neurohormonal factors as regulatingother aspects and joint regulation of still other aspects. Assuch these observations have driven a shift of thinking of chronic heart failure as a progressive irreversible diseaseprocess to a potentially treatable entity.

One intriguing concept generated by the ndings of thesestudies is the conclusion that signicant hemodynamic un-loading, as provided only by LVADs, is necessary to induceprofound reverse structural remodeling, in which caseLVADs could assume a central role in any highly effectiveor curative strategy for patients with severe heart failure.A possible alternative would be to unravel the long soughtafter, highly elusive, molecular links between mechanicalstress, and the regulation of c ell growth and target thesethrough pharmacologic means. 136,137

Clinically, current experience would suggest that for pa-tients with longstanding cardiomyopathy only few will dem-onstrate substantial and sustained cardiac recovery duringLVAD support. Future efforts to understand why this recov-ery is neither complete nor permanent, especially when theheart is re-exposed to hemodynamic stress, will continueto reveal new insights and could result in development of more effective, potentially curative treatments for this grow-ing population of suffering patients. Approaches in whichLVAD support is combined with on e or more other treatmentmodality, such as a drug therapy, 108 cell therapy, 138,139 orpossibly a passive restraint device 140 to prevent post-

LVAD explant remodeling may prove particularly fruitful.

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