Review Article

LVAD-Induced Reverse Remodeling: Basic and Clinical

Implications 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 with
end-stage heart failure. Early in the course of LVAD use as a bridge to transplant, it became evident
that some patients exhibit substantial recovery of ventricular function, which led to the concept of reverse
remodeling.
Methods and Results: Herein we summarize and integrate insights derived from a multitude of studies
that have investigated how LVAD support inuences ventricular structural, cellular, extracellular matrix,
molecular, biochemical, and metabolic characteristics of the end-stage failing heart. The focus includes
a review of the extent and sustainability of reverse remodeling, the important advances in understanding
of the pathophysiology of heart failure derived from these studies and the implications of these ndings for
development of new therapeutic strategies.
Conclusion: In brief, studies of LVAD-heart interactions have led to the understanding that although we
once considered the end-stage failing heart of patients near death to be irreversibly diseased, when given
sufcient mechanical unloading and restoration of more normal neurohormonal milieu, a relatively large
degree 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 other
aspects. As such these observations have driven a shift of thinking of chronic heart failure as a progressive
irreversible disease process to a potentially treatable entity.
Key Words: Heart failure, extracellular matrix, hypertrophy, right ventricle, excitation-contraction
coupling.
With improved technology, increasing clinical experi-
ence, and expanding indications for use, left ventricular as-
sist devices (LVADs) are assuming a greater 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 evident
that 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 fashion
have progressed rapidly back to heart failure or have died of
heart failurerelated complications. Therefore, LVADs are
not generally used with the intention of bridging patients
to recovery. However, knowledge has emerged from studies
of hearts supported by LVADs that provides insights into
the basic mechanisms of ventricular remodeling and possi-
ble limits of ventricular recovery.
1115
In general, it was
these studies that spawned the concept of reverse remodel-
ing,
16
now recognized as an important goal of many heart
failure 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 received
October 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, 8
Corporate Dr, Orangeburg, NY 10962.
1071-9164/$ - see front matter
2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.cardfail.2005.10.012
227
Journal of Cardiac Failure Vol. 12 No. 3 2006
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 Many
Increased 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
-Ca
21
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
50
Caveolin expression increased
51
Neurohormones (all decreased) Epinephrine 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 Dystrophin 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-3b 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, left 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.
228 Journal of Cardiac Failure Vol. 12 No. 3 April 2006
profound, impacting on nearly every aspect of myocardial
and systemic properties that is pathologically altered in
the 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 this
table nor possible to include every reference published on
this rapidly growing eld. This review attempts to summa-
rize and integrate insights derived from these studies as
they 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 responsibility
for pumping blood to restore normal cardiac output and
blood pressure (Figs. 1 and 2) and allow reduction (or elim-
ination) of the need for toxic levels of pressor and inotropic
support.
4,23,25,26
With LVADs of most designs, this is
achieved by withdrawing blood from the left ventricle or
atrium and returning it to the arterial system.
In addition, there are at least 2 benecial secondary
effects of LVAD support. First, based on their anatomic
connections, LVADs are pumps functionally positioned in
parallel to the normal left ventricle. As such, they divert
blood from the left ventricle and provide profound LV pres-
sure and volume unloading. This also results in reductions
in pulmonary venous and arterial pressures and reduced
pulmonary vascular resistance (ie, right ventricular afterload
is reduced).
17,23
Second, by normalizing blood pressure and
cardiac output, LVAD support improves perfusion to all
body organs, which results in improved autonomic func-
tion
100
and normalization of the neurohormonal and cyto-
kine milieu that is present in heart failure. The potential
signicance of these secondary effects may have been unan-
ticipated by early LVAD designers, but their profound
importance is now widely recognized. Heart failure is con-
sidered a systemic disease that affects many organs because
of hypoperfusion and the abnormal neurohormonal and
cytokine milieu; normalization of this milieu by LVADs
promotes systemwide recovery.
Not all secondary effects of LVAD support, however, are
benecial. 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, normal
or low pulmonary venous pressure with high central venous
pressure) and RV distention occur in as many as 20% to
30% of LVAD recipients.
21,22
In many instances this can
be 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 taken
advantage of these differential effects on the LV and RV
to 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, to
neurohormonal factors, or to both.
Ventricular Structural Reverse Remodeling
Ventricular structure is characterized by LV muscle
mass and the end-diastolic pressure-volume relationship
100 150 200
0
20
40
60
80
100
CHF
CHF + LVAD
P
r
e
s
s
u
r
e

(
m
m
H
g
)
Volume (ml)
100
150
200
250
V
o
l
u
m
e

(
m
l
)
0.5 Sec
0
50
100
150
P
r
e
s
s
u
r
e

(
m
m
H
g
)
CHF CHF+LVAD
Fig. 1. Acute hemodynamic effects of left ventricular assist device
(LVAD) support schematized in pressure-volume loops (top) and
time plots of ventricular pressure, aortic pressure, and ventricular
volume (bottom). Before LVAD, end-diastolic pressure and vol-
ume are high, whereas aortic pressure is low. When an LVAD
pumping in synchrony with the native heart beat (with a pulsatile
pump such as the HeartMate) is turned on, end-diastolic pressure
and volume drop dramatically, and cardiac output is derived exclu-
sively from the LVAD. Peak ventricular systolic pressure also falls
dramatically, aortic pressure rises dramatically and the aortic
valve does not open. Ventricular contractions serve primarily as
a booster pump to ll the LVAD. Acutely, ventricular end-systolic
pressures 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, the
heart reverse remodels and these curves shift leftward toward
more normal, smaller volumes. Curves obtained from a computer
simulation
141
modied to include a pulsatile LVAD.
LVAD-Induced Reverse Remodeling Burkhoff et al 229
(EDPVR).
117
Although studied for decades previously, it
was not until the seminal work of Pfeffer and colleagues
that it was demonstrated in experimental heart failure that
this relationship shifts rightwards toward larger volumes
in 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 extracellular
matrix changes in response to the abnormal stresses and
neurohormonal stimulation present in heart failure. Similar
shifts of the EDPVR in human heart failure were soon con-
rmed in both ischemic and idiopathic cardiomyopa-
thies.
119,120
Interventional studies in animals and humans
suggested that the extent of remodeling could be limited,
at least after acute myocardial infarction, with the use of
vasodilators.
121
However, in the 1980s and early 1990s, it
was generally believed that after the heart was markedly di-
lated, no form of therapy could meaningfully reverse that
process, which led to the generally held concept of irrevers-
ible, end-stage cardiomyopathy.
Among the initial case reports of patients undergoing
prolonged LVAD support, a chest X-ray published by Fraz-
ier
4,122
showed a small cardiac silhouette after prolonged
LVAD support suggesting, in contrast to the preoperative
severe chamber dilation, the presence of a nondilated heart.
It was recognized that this nding could simply have been
due to the unloading provided by the pumping LVAD,
which decompressed the would-be dilated heart, particular-
ly in the acute setting.
32,34
However, this was subsequently
shown not to be the case after chronic support through ex-
amination of the EDPVRs.
16
LV EDPVRs were measured
from human hearts explanted at the time of orthotopic
transplantation in patients requiring LVAD support, from
those not requiring LVAD support, and from several normal
human hearts not suitable for transplant (Fig. 3A). Com-
pared with normals, EDPVRs of nonLVAD-supported
hearts were shifted toward markedly increased volumes (re-
modeling). In contrast, EDPVRs from LVAD-supported
Fig. 2. Parasternal long axis echocardiograms taken from a patient
about 1 week after implantation of a pneumatic left ventricular as-
sist device (LVAD) during a venting cycle when the LVAD is
temporarily off (A) and minutes after the device is turned back
on (B). With the device off, the LVis dilated. With the device turned
on, the LV size decreases markedly (volume unloading), although
the RV remains loaded. LV, left ventricle; RV, right ventricle; IC,
LVAD inow conduit; Ao, aorta. Adapted from Levin et al.
16
C
E
D
0.1 mm
0 50 100 150 200 250 300
0
20
40
60
80
100
120
Normal
non-LVAD
LVAD
0-40
LVAD
40+
LV Volume (ml)
L
V

P
r
e
s
s
u
r
e

(
m
m
H
g
)
0 40 80 120 160
0
100
200
300
400
Duration of LVAD Support (days)
V
3
0

(
m
l
)
A
B
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 average
EDPVRs from normal human hearts, from failing hearts not sup-
ported with LVAD, hearts supported with an LVAD for less than
40 days and hearts supported with in LVAD for more than 40
days. (B) Heart size, indexed by V30, the volume required to
achieve an end-diastolic pressure of 30 mm Hg as a function of
duration of LVAD support from individual hearts (see a insert
for symbol key). Also shown are values from normals and from
failing hearts not supported by LVAD. Underlying the reduction
in heart size is regression of cellular hypertrophy. (C) Cross-section
of normal human myocardium. In chronic heart failure (D), the
myocytes 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 CE were xed in an unloaded
state. All gures from Madigen et al.
27
230 Journal of Cardiac Failure Vol. 12 No. 3 April 2006
hearts were more similar to normal. The near-normal posi-
tion of these EDPVRs reected a shift of the relations from
high to signicantly lower volume. We referred to this shift
of the EDPVR back toward normal as reverse remodeling.
16
The time course of reverse structural remodeling has been
inferred by plotting the position of the EDPVR (indexed by
thevolume at a xedpressure of 30mmHg, V
30
) as a function
of LVADsupport (Fig. 3B).
27
This relationassumeda roughly
exponential time course with average time constant of 30.8
days, with the process reaching its maximal effect by about
90 days. On average, however, the hearts did not return to
completely normal size. V
30
averaged about 280 mL without
LVAD 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 generally
dilated, though not as signicantly as the LV. RV V
30
is
about 80 mL in normal hearts and reaches about 150 mL
in cardiomyopathy.
18
In contrast, RV V
30
of LVAD support-
ed hearts also averages about 150 mL, indicating that the
structural reverse remodeling is not generally observed in
this chamber.
18
Because central venous pressures remains
elevated during LVAD support,
1722
the lack of reverse
structural remodeling in the RV at the same time when re-
verse structural remodeling is strongly present in the LV
signies that reverse structural remodeling is primarily me-
diated the hemodynamic unloading and not by normalized
neurohormonal milieu. Because LVADs also reduce RV
afterload,
17,23
the factor regulating reverse structural
remodeling can even more specically be targeted as the re-
duction in preload. Additional support for this hypothesis is
provided by the ndings that (1) on the rare occasion when
an LVAD inow valve failed the heart would be reloaded
and would redilate (rightward shifted EDPVR) despite
maintenance of normal forward cardiac output and blood
pressure
31
and (2) that indeed RV V
30
regresses toward nor-
mal in hearts of patients receiving right ventricular device
support.
123
Similar univentricular effects are observed on
regression of free wall mass and cellular hypertrophy
(Fig. 3C3E).
18,27,29,30,32,3539
The time course of change
of LV myocyte cell dimension paralleled changes in mass
and V
30
,
27
but no such changes were observed in the RV.
18
Finally, in addition to normalized myocyte diameter,
LVAD support induces normalization of the cytoskeleton
as evidenced by normalization of sarcomeric proteins,
vinculin, desmin, and b-tubulin.
38,6771
Improved Myocardial Function
In addition to the effects on structure, studies of trabeculae
and myocytes isolated from LVAD supported hearts also
demonstrate 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 to
increased frequency of stimulation (normalized force-
frequency relationship, FFR) and to b-adrenergic stimula-
tion. These ndings were subsequently conrmed in isolated
trabeculae.
18,19,4345
Recovery of the FFR correlated with
improved expression of calcium cycling genes and improved
calcium accumulating 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 with
chamber-specic normalized expression of genes involved
with calciumcycling.
18
In contrast, b-adrenergic responsive-
ness improved in myocardium of both RV and LV. These
ndings suggested that some aspects of functional recovery
(eg, FFRand gene expression of calciumhandling genes) are
primarily regulated by hemodynamic factors, whereas other
factors (eg, b-adrenergic signaling) are primarily regulated
by normalized neurohormonal milieu.
Extracellular Matrix
In addition to structural and functional changes, LVAD
support is also associated with changes in the characteris-
tics and metabolism of the extracellular matrix. In contrast
to other aspects, however, extracellular matrix properties do
not change uniformly in a manner indicative of conversion
back to the normal state. Indeed, several studies show that
myocardial collagen content increases during mechanical
unloading above the already abnormal levels observed in
the chronic failing state.
27,32,34,73
In contrast, results of
a few studies indicated the opposite.
36,74
In our recent study
we showed that LVAD support was associated with a signif-
icant increase in total and especially crosslinked collagen
deposition in LV myocardium.
20
MMP-1 and MMP-9 levels
and activity (matrix metalloproteinases, which are enzymes
involved in breakdown of collagen), which are increased in
the failing state, tended to decrease following LVAD sup-
port. Concomitantly, TIMP-1 (tissue inhibitors of metallo-
proteinases) levels increased tremendously after LVAD
support, leading to a normalization of the MMP-1/TIMP-
1 ratio. In addition, myocardial tissue levels of angiotensin
I and II, known regulators of myocardial collagen synthesis,
increased during LV unloading and the ratio of type I to
type III collagen shifted (abnormally) to the more stiff
type I collagen. In aggregate, these ndings suggested
that 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 in
myocardial stiffness, which we speculated could be a factor
contributing 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 (as
will be discussed later in this article). Findings in the RV
were somewhat mixed, with most aspects trending in the
same direction as in the LV, but typically not reaching sta-
tistical signicance. This somewhat ambiguous picture lead
LVAD-Induced Reverse Remodeling Burkhoff et al 231
us to conclude that both neurohormonal and mechanical
factors likely contribute importantly to extracellular matrix
metabolism.
Molecular, Biochemical, and Metabolic Changes
As alluded to previously, the structural and functional
improvements in myocytes and ventricular chamber have
as their basis normalized expression of certain genes and
posttranslational regulation of certain proteins that improve
cellular functions and metabolism. It is well known that
a multitude of changes in myocardial gene expression occur
in heart failure that are generally considered to reect a shift
from the normal adult to a fetal gene program.
124
Teliolog-
ically, this shift is believed to be driven by the mechanical
and neurohormonal stresses of heart failure, features of
which partially mimic the fetal environment. Compared
with adult myocytes, fetal myocytes have a greater ability
to undergo cell division. The changes associated with heart
failure can thus be viewed as a response that reverts the
genotype to a state in which the cells were more readily
able to increase cell number and normalize wall stress.
Because the transformation to the fetal state is incomplete,
the mechanical and neurohormonal environment drives
hypertrophy and, ultimately, apoptosis (programmed cell
death).
125,126
The inuence of LVAD support on gene expression, pro-
tein content, and protein function has been studied by several
groups. As discussed previously, early studies showed nor-
malization of expression and function in the LV (not the
RV) of proteins involved with calcium handling known to
be abnormal and contribute to contractile dysfunction in heart
failure. 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 toward
normal 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-3beta
pathway is not activated during LVADsupport and concluded
that other signaling pathways must be responsible for the
improvement of cellular function and cell survival.
93
Studies of the inuence of LVAD support on myocardial
metabolism have also yielded mixed results. On the one
hand, improvement of overall myocardial mitochondrial
function,
78,83
normalized expression of uncoupling protein
3
56
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 carnitine
palmityl transferase-1) are not normalized during mechan-
ical unloading.
56
Thus it appears that LVAD support only
partially reverses depressed expression of genes involved
in metabolism in the failing human heart.
More recently, microarray GeneChip platforms have
been used to survey changes in transcription patters in
response to LVAD support.
103
Hall et al showed that 22
genes were downregulated, whereas 85 genes were upregu-
lated after LVAD support.
104
Genes involved in regulation
of myocardial hypertrophy and vascular signaling were sig-
nicantly downregulated. Using this technique, our group
showed that calcium-handling genes were upregulated,
whereas genes involved with regulation of myocardial -
brosis did not change on the transcription level.
102
Margu-
lies et al identied 3088 transcripts that exhibited abnormal
abundance. As a consequence of LVAD support, only 11%
of these genes exhibit partial recovery and only 5% showed
true normalization.
101
This latter study in particular rein-
forced the notion that although normalization of specic
genes 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 most
recent 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 compared
with those in which recovery was insufcient.
72
These
investigators 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 in
identifying the number of proteins that are either present
in abnormal quantities or whose function is abnormal.
Mechanisms of Reverse Remodeling
Are Unknown
The biology of how cardiac muscle responds to altera-
tions in mechanical stress remains largely unknown. Most
prior research has been devoted to understanding the impact
of increased afterload as occurs in myocardial hypertrophy.
Yet, after more than 40 years of physiologic, biochemical,
and molecular research, it is still not fully understood
how stress or strain regulate gene expression, assembly of
sarcomeric and cytoskeletal proteins, and modify calcium
cycling and function of other ion channels. Membrane
bound macromolecules that link extracellular matrix and
intracellular elements (integrins) and membrane bound
components of a multitude of signaling cascades (eg, path-
ways involved in a- and b-adrenergic signaling, growth
hormones, phosphokinases) have all been implicated in
the hypertrophic response through their impact on many
signaling 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 that
the mechanisms leading to normalization of myocardial ab-
normalities present in heart failure during mechanical un-
loading by LVADs reects normalization of these very
same signaling cascades invoked during hypertrophy as op-
posed to recruitment of pathways specic for the generation
of atrophy. Although evidence available thus far is
232 Journal of Cardiac Failure Vol. 12 No. 3 April 2006
consistent with our assumption, this is an assumption that
has yet to be tested. So far, tissue derived from patients un-
dergoing LVAD support provides the best opportunity to
study this because of the paucity of experimental models
of myocardial unloading or reverse remodeling.
Effects of Different LVAD Flow Patterns
on Reverse Remodeling
In general, 2 different classes of LVADs are now in use
for long-term support: pulsatile and non-pulsatile LVADs.
9
During the last decade, pulsatile LVADs were dominant in
clinical use, but nonpulsatile devices are now the dominant
form 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 al
show that the inammatory response measured by tumor
necrosis factor-a and C5a was signicantly more increased
after implantation of a nonpulsatile LVAD than with a pul-
satile LVAD.
66
Potapov et al showed that biochemical
marker of brain damage were similar between the 2
LVAD types in the rst 14 days after implantation,
127
sim-
ilar to the study from Vatta et al, who demonstrated reversal
of disruption of dystrophin with either pulsatile or nonpul-
satile LVADs.
69
Only 1 study evaluated hemodynamic
effects during long-term support with nonpulsatile and pul-
satile LVADs.
23
It was found that LV pressure unloading
was similar between these 2 types of LVADs, whereas LV
volume unloading was signicantly more pronounced
with a pulsatile device. Most recently, Thohan et al showed
that although there are differences between these 2 classes
of devices with regard in magnitude of unloading, both
forms of support were equally effective in normalizing
cell size and tumor necrosis factor-a levels.
41
These nding
might provide important insights into the remodeling
process with different LVAD support.
128
Clinical Evidence of LVAD-Induced Ventricular
Contractile Recovery
Although recovery of LV function is commonly observed
when LVADs are used in the setting of acute heart failure
syndromes,
5,111114
the concept of recovery of ventricular
function in patients with chronic heart failure after LVAD
has been described only recently. It is noteworthy, however,
that all of the research described concerning the relatively
large degree of structural and functional reverse remodeling
in chronic heart failure was entirely spawned by early clin-
ical observations that signicant recovery of LV function
occurs during LVAD support.
The rst reported case of cardiac functional recovery af-
ter LVAD support involved an otherwise healthy young man
with an idiopathic cardiomyopathy.
2
At the time of in-
tended transplant, the native heart was observed to have
normal hemodynamic measurements with a normal ejection
fraction. The transplant was aborted, the LVAD explanted
and the patient became the rst BTR with a HeartMate
LVAD. After LVAD removal, however, the heart progres-
sively redilated to its original pre-LVAD condition and
unfortunately the patient succumbed to heart failure. The
initial elation of investigators was dashed by the realization
that the recovery could not be sustained when the heart was
re-exposed to the hemodynamic load of the circulation.
Since our rst experience, several groups have reported
their clinical experiences concerning recovery of ventricu-
lar function post LVAD support.
129
The results have varied,
with some centers reporting a high frequency of LVAD
explantation followed by sustained recovery and others
only describing rare cases of myocardial recovery.
Based on a retrospective chart review, we observed only
5 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 patients
eventually developed recurrent heart failure, with 2 patients
requiring a second LVAD for recurrent heart failure and the
remaining 3 patients dying of progressive heart failure.
We also used exercise stress testing (including exercise
hemodynamics, echocardiography, and oxygen consump-
tion), to identify potentially recovered patients.
3
Patients
underwent cardiopulmonary exercise testing with the
LVAD providing full support. Exercise was repeated in
those patients who were able to tolerate weaning of ow
to about 2 L/minute. Patients were considered for device
explantation if they were able to exercise with minimal
LVAD support and achieve a maximal oxygen consumption
of 20 mL$kg$minute or peak cardiac output greater than
10 L/minute. Thirty-nine patients underwent cardiopul-
monary stress testing approximately 3 months after LVAD
implant according to this strategy. Weaning to partial sup-
port was achieved in only 7 of the 39 patients. Peak oxygen
consumption declined in these 7 patients from an average of
17.3 mL O
2
$kg$minute during full support to 13.0 mL
O
2
$kg$minute during partial support. The LVAD was ex-
planted in only 1 patient demonstrating partial recovery
due to device infection. This patient subsequently required
reinsertion of another LVAD.
Another strategy for identifying potential responders has
been 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 with
dilated cardiomyopathy in whom cardiac output increased
and pulmonary capillary wedge pressure maintained below
15 mmHg in response to dobutamine; these 9 patients were
successfully weaned.
40
Six of these patients survived for at
least 1 year, but all subsequently died or required transplant
(Torre, personal communication).
El Banayosy et al observed that only 1 of 13 LVAD
patients could be successfully weaned, in whom hemody-
namic measurements improved during LVAD support.
106
Helman et al described recurrent remodeling in two patients
2 and 6 month after primary successful LVAD explantation
with the need for recurrent LVAD implantation.
105
The
LVAD-Induced Reverse Remodeling Burkhoff et al 233
mechanical circulatory support device database from 2004
showed that LVADs were used as bridge-to-transplant in
75.5% of cases, as destination therapy in 8.4% of cases
and as BTR in 5.8% of cases.
1
Of the 24 patients from
the BTR group, 7 died before transplant, 2 did not recover
after LVAD placement and had to be transplanted, and in
only 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 after
device explant are not described and may not be uniform at
the different participating centers.
In contrast to these reports, the Berlin Heart Group
reports a higher frequency of LVAD-induced myocardial
recovery in patients with chronic idiopathic cardiomyo-
pathy.
107
More than 33% of their patients with dilated car-
diomyopathy have undergone device explantation for
recovery. Over a 10-year period, 33 patients with chronic
nonischemic cardiomyopathy supported with an LVAD un-
derwent explanation after recovery. The majority of these
patients have sustained improvement with a 5-year survival
of 85%. Recurrence of heart failure was observed in 32% of
patients by 2 years after device explantation. Six patients
required cardiac transplantation. One patient died of heart
failure and 3 patients died of non-cardiac causes after de-
vice explantation. Predictors of sustained recovery included
LV end-diastolic dimension less than 55 mm and ejection
fraction 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 O3 years
post explant of 92%). Hetzer et al also observed that opti-
mal improvement in LV size and function occurred within
approximately 90 days of LVAD implantation, but noted
a gradual deterioration with longer periods of support.
130
The LVADWorking Group Recovery Study, a multicenter
study including the 8 largest LVAD groups in the United
States (Baylor, Cleveland Clinic, Columbia, Temple, Texas
Heart Institute, and Universities of Michigan, Minnesota,
Pittsburgh) was established in response to these contrasting
reports of recovery during LVAD support.
109
In this pro-
spective study, 67 LVAD patients underwent monthly as-
sessment of cardiac function using echocardiography at
full and partial support. Fifty-ve percent of the patients
had 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. LVEF
rose from an average of 17% preimplant to 34% at 1 month
after implant during partial ventricular assist. Thirty-one
percent of patients had ejection fractions O40%. 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 successful
LVAD explant. One patient with chronic heart failure had
partial recovery but underwent device explantation because
of device malfunction. This patient quickly deteriorated
with ejection fraction falling from 35% to 20%.
Strategies to Enhance Ventricular
Contractile Recovery
Another group reporting success in bridging cardiomyo-
pathic patients to full recovery and LVAD explant is the
Hareeld group.
108,115
Led by Sir Magdi Yacoub, this
group 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 animal
models to induce skeletal and cardiac muscle hypertrophy
and 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 Hareeld
with this protocol, 70% (11 patients) demonstrated suf-
cient recovery to allow device explantation. Clenbuterol
was stopped just before device explantation and not re-
sumed. After 3 years of follow-up, the average reported
ejection fraction of theses patients remains 60% to 65%.
To date, only 1 patient is reported to have demonstrated
clinical deterioration, and that was associated with signi-
cant alcohol intake. More recently, this group found that
clenbuterol induces insulin-like growth factor I (IGF-I) in
cardiac myocytes in vitro.
134
They subsequently examined
changes in IGF-I expression in patients who recovered after
LVAD support combined with clenbuterol treatment.
96
They found that patients with low IGF-I mRNA levels at
implantation showed signicant increase during recovery
and those with high IGF-I mRNA at implantation remained
high. In both groups, levels returned to normal by 1 year
after explantation. They concluded that elevated myocardial
IGF-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 determine
whether the results obtained at Hareeld can be replicated
by US centers (ie, Hareeld Recovery Protocol Study).
Conclusion
Shifts of ventricular and myocardial properties back to-
ward normal observed during LVAD support are collectively
referred 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, ventricular
mass and structure), this is not a ubiquitous process. Impor-
tant examples of myocardial or ventricular properties that
do not regress toward normal during LVAD support include
abnormal extracellular matrix metabolism, increased tissue
angiotensin levels, myocardial stiffening, and partial recov-
ery of genes involved with metabolism. Indeed, broad sur-
veys of myocardial gene expression using gene chip
technology reveal that expression of only a small percentage
of abnormally expressed genes normalizes.
101
234 Journal of Cardiac Failure Vol. 12 No. 3 April 2006
In addition, LVAD support cannot correct an aquired or
inherited genetic 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 the
infracted tissue with contracting myocytes. These realities
may serve to establish theoretical and practical limits to
the extend and sustainability of LVAD-induced reverse
remodeling.
Nevertheless, studies of LVAD-heart interactions have
led to the understanding that although we after considered
the end-stage failing heart of patients near death to be irre-
versibly diseased, when given sufcient mechanical un-
loading and restoration of more normal neurohormonal
milieu, a relatively large degree of myocardial recovery is
possible. Comparisons of effects on right and left ventricles
have provided mechanistic insights by implicating hemody-
namic unloading as primarily regulating certain aspects of
reverse remodeling, neurohormonal factors as regulating
other aspects and joint regulation of still other aspects. As
such these observations have driven a shift of thinking of
chronic heart failure as a progressive irreversible disease
process to a potentially treatable entity.
One intriguing concept generated by the ndings of these
studies is the conclusion that signicant hemodynamic un-
loading, as provided only by LVADs, is necessary to induce
profound reverse structural remodeling, in which case
LVADs could assume a central role in any highly effective
or curative strategy for patients with severe heart failure.
A possible alternative would be to unravel the long sought
after, highly elusive, molecular links between mechanical
stress, and the regulation of cell growth and target these
through 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 during
LVAD support. Future efforts to understand why this recov-
ery is neither complete nor permanent, especially when the
heart is re-exposed to hemodynamic stress, will continue
to reveal new insights and could result in development of
more effective, potentially curative treatments for this grow-
ing population of suffering patients. Approaches in which
LVAD support is combined with one or more other treatment
modality, such as a drug therapy,
108
cell therapy,
138,139
or
possibly a passive restraint device
140
to prevent post-
LVAD explant remodeling may prove particularly fruitful.
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