European Heart Journal (2001) 22, 534–540
doi:10.1053/euhj.2001.2613, available online at http://www.idealibrary.com on
Clinical Perspective
A novel strategy to maximize the efficacy of left
ventricular assist devices as a bridge to recovery
Introduction
Heart failure is one of the major causes of morbidity
and mortality in both developed and developing
countries[1,2]. Despite advances in the medical
management of heart failure the only real effective
form of therapy for patients with advanced heart
failure is cardiac transplantation. Heart transplantation is, however, becoming increasingly limited by
the shortage of donor organs. There is, therefore, a
pressing need for the development of alternative
therapies for these patients.
Left ventricular assist devices are being used in
patients with advanced heart failure, generally as a
bridge to transplantation. A small number of these
patients have shown a significant improvement in
myocardial function[3], which has been sufficient in
some cases to allow explantation of the device[4,5].
The exact proportion of these patients is still
unknown, but is thought to be very small[6]. In
addition, the mechanisms involved are largely
unknown. Maximizing the rate of recovery depends
on understanding the cellular, molecular and biophysical changes and the mechanisms responsible for
progression and/or regression of heart failure in these
patients. Although heart failure is known to be a
multifactorial disease, there is now compelling evidence that a process of progressive hypertrophy or
remodelling[7–16] plays a major part. Although hypertrophy starts as a physiological adaptive response to
increased load from a variety of causes, it becomes
maladaptive and results in a self perpetuating pathological process of remodelling, ending in terminal
heart failure. An intriguing aspect of this process is
that it is not unidirectional, but can be traced
back through a process of ‘reverse remodelling’[17,18]
towards normality.
As the initial stimulus is almost invariably stretching of the myocardium, it follows that unloading with
Manuscript submitted and accepted 17 January 2001.
Correspondence: Sir Magdi H. Yacoub FRS, Professor of Cardiothoracic Surgery, Heart Science Centre, Imperial College of Science
Technology & Medicine, Harefield, Middlesex UB9 6JH, U.K.
0195-668X/01/070534+07 $35.00/0
a left ventricular assist device plays an important role
in reverse remodelling. However, on its own, unloading appears to be inadequate. We therefore evolved a
strategy of combination therapy, aiming at inducing
maximal regression of pathological hypertrophy, followed by induction of physiological hypertrophy[19]
of both cardiac and skeletal muscle[19–21]. In this
article, the rationale and early results of this strategy
are presented.
The process of remodelling
Remodelling involves different components of the
myocardium which include the cardiomyocyte, the
matrix, endothelial cells and fibroblasts.
The cardiomyocytes change their phenotype with
marked enlargement in their size which is more
pronounced in the long axis as compared to the width
or depth[13–16] (Fig. 1). This is associated with a
deterioration in contractile function[22,23] (Fig. 2)
(both contraction and relaxation and a response to
catecholamine)[24], and induction of a specific gene
programme involving several groups of genes[25–28].
These include genes encoding sarcomeric and
cytoskeletal proteins, calcium handling proteins,
metabolic enzymes, ion channels, secreted cytokines
and growth factors and enzymes involved in the
apoptic pathway. Abnormalities in the cytoskeletal
proteins and their regulators appear to play an
important role in familial and acquired[29,30] forms of
dilated cardiomyopathy. Of particular interest in this
context are the LIM proteins[31] which mediate interaction between the cytoskeleton and multiprotein
transcription factors. Mice deficient in muscle LIM
(MLP knock-out mice) develop dilated cardiomyopathy with almost all the characteristics of human
dilated cardiomyopathy[32]. It is of interest that a
recent study has reported decreased MLP expression
in patients with dilated and ischaemic cardiomyopathy[33]. A link between changes in cytoskeletal
proteins and calcium handling is suggested by the fact
that an animal model combining deficiency of MLP
and the calcium handling protein phospholamban did
2001 The European Society of Cardiology
Clinical Perspective
535
Figure 1 Isolated ventricular myocytes from patients at the time of insertion of a left
ventricular assist device (LVAD) (middle horizontal panel) showing severe hypertrophy as
compared to normal controls (top horizontal panel). Bottom panel shows ‘normalization’ of the
size of the myocytes post left ventricular assist device.
90
R90 0·92 s
Pre-LVAD
R
0·46 s
Post-LVAD
Figure 2 Sample traces from contraction of left ventricular trabeculae
prior to and after 8 months of left ventricular assist device (LVAD)
support combination. Time to 90% relaxation (R90) was slower prior to
left ventricular assist device, R90 =0·925 vs 0·46 after left ventricular
assist device. Preparations were stimulated at 0·5 Hz at 32 C.
not develop cardiomyopathy[34]. This is supported by
early observations in our bridge to recovery programme, that haemodynamic recovery is associated
with a reduction in expression of phospholamban and
an increase in SERCA2 (Fig. 3) and sarcoplasmic
reticulum calcium content (Fig. 4).
The extracellular matrix is in a dynamic equilibrium regulated by a family of enzymes termed
metalloproteinases and their inhibitors (tissue
inhibitors of metalloproteinases). Differential changes
in these enzymes have been reported in the myocardium of patients with dilated cardiomyopathy and
heart failure[35] and are thought to play an important
role in the process of remodelling[36] and possibly
recovery.
Pathological hypertrophy is associated with
increased fibrosis and collagen remodelling of the
myocardium secondary to the proliferation and
Eur Heart J, Vol. 22, issue 7, April 2001
536
M. H. Yacoub
Relative ratio SERCA2a vs
phospholamban RNA
1·0
0·9
0·8
0·7
0·6
0·5
0·4
0·3
0·2
0·1
0
Implant
4 month
22 month 24 month 25 month
(pre-Clen) (post-Clen) (explant)
Figure 3 Serial changes in the relative ratio of SERCA2a to
phospholamban RNA following insertion and explantation of a left
ventricular assist device.
increased secretory activity of cardiac fibroblasts[37].
The renin angiotensin aldosterone system is thought
to play an important role in this process of fibrosis[38,39]. Currently high throughput analysis of gene
expression through gene chip technology[26] and the
use of proteomics[27] is being used to expand our
knowledge of the changes in gene expression associated with ‘remodelling’ and heart failure. Such
knowledge could help in monitoring molecular
markers of recovery and possibly stimulate novel
targets for pharmacological interventions.
Mechanisms of remodelling
Sarcoplasmic reticulum Ca content
–1
(µmol.l non-mitochondrial volume)
Although the exact molecular mechanisms of
remodelling are still not fully known, several
mediators amenable to pharmacological interventions
have been implicated. These include the reninangiotensin-aldosterone system[38–41], the 1-receptor
system[19–42], endothelins and cytokines[43,44]. Most of
25
15
5
Control
Pre-LVAD
Post-LVAD
Figure 4 Changes in levels of sarcoplasmic reticulum
Ca content after left ventricular assist device (LVAD)
insertion.
Eur Heart J, Vol. 22, issue 7, April 2001
these are closely linked to the process of loading or
stretching of the myocardium. The renin-angiotensinaldosterone system has been shown to have potentially harmful effects on the myocytes, fibroblasts,
and endothelial cells. Similarly, several studies have
shown that increased sympathetic activity, particularly those involving 1-receptor function, are maladaptive and involved in the progression of human
heart failure[42,45]. This is supported by the proven
beneficial effects of beta-blockers[45] especially those
which are 1 specific, such as metoprolol. In animal
models, administration of 1 agonists produces
pathological hypertrophy associated with fibrosis and
can produce apoptosis of cardiac myocytes[19,46]. In
contrast, 2 agonists can produce physiological
hypertrophy[19] and do not cause apoptosis[46]. In
addition, transgenic mice over expressing 1 receptors
die prematurely while those over expressing 2 receptors (25 fold) have enhanced myocardial function
with a normal survival[47].
Activation of the immune system with increased
myocardial expression and circulatory levels of several cytokines, such as TLR[48], interleukin 6 and
tumour necrosis factor[43,44], have been implicated in
the progression of heart failure through their direct
effects on the myocardial cells producing contractile
dysfunction and possibly apoptosis[28]. In the current
bridge to recovery programme we have used a combination of mechanical support with pharmacological
manipulation of two of the four putative mechanisms
mentioned above.
Combination therapy
The rationale of the combination therapy is to
achieve maximal unloading of the myocardium
Clinical Perspective
combined with pharmacological therapy, aimed at
remodelling reversal, followed by stimulation of the
development of physiological hypertrophy.
Although pusher-plate implantable left ventricular
assist devices produce significant unloading of the left
ventricle by drawing blood from the apex, their
function is not co-ordinated with native left ventricular contraction, which can occur at a phase when
both the inlet valve of the device and the native aortic
valve are closed. This results in isometric ventricular
contraction, which is energy consumptive and can
cause excessive stretching of the myocardium, particularly in the presence of systemic hypertension
which can occur following left ventricular assist
device insertion. Regurgitation of the inlet valve of
the left ventricular assist device can also result in
systolic and diastolic stretching of the myocardium.
The latter is known to induce Brain Natriuretic
Peptide (BNP)[49] which is only expressed in
hypertrophied or failing myocardium.
Several drugs currently in use for the treatment of
heart failure can help the process of unloading and
actively produce reverse remodelling. These drugs
include beta-blockers and drugs known to modulate
the renin-angiotensin-aldosterone system. Betablockers have multiple beneficial effects: slowing
heart rate, lowering blood pressure, as well as a direct
effect on the myocardium by reversing remodelling
and upregulating -receptors. The combination of
ACE inhibitor and angiotensin 1 receptor antagonists
has the advantage of full blockade of the receptors,
together with enhanced endothelial function due to
increased concentrations of bradykinin produced by
ACE inhibition[41]. The beneficial effect of combining
these drugs is supported by clinical and experimental studies[41,50]. Apart from the effect on reverse
remodelling, these drugs have a direct effect on the
sarcoplasmic reticulin[51], which improves calcium
handling and diastolic function. The addition of
spironolactone has been shown to enhance survival
in heart failure[52] and reduce myocardial fibrosis in
these patients[53].
Once maximal reverse remodelling has been
achieved, a programme of inducing physiological
hypertrophy is instituted. This consists of administration of the 2 agonist clenbuterol which is known
to induce skeletal muscle hypertrophy and improve
performance[21] and also to stimulate physiological
‘myocardial hypertrophy’[19,20]. As explained earlier,
2 agonist do not cause apoptosis[46] or increased
mortality in animal models[47]. During administration
of clenbuterol, 1 receptor antagonist therapy is continued. The action of clenbuterol on the structure and
function of skeletal muscles[21] could be particularly
valuable in patients with heart failure who are known
537
to have significant skeletal muscle abnormalities.
During this period, an active exercise programme is
administered, again to help the process of physiological hypertrophy.
Monitoring recovery
Evidence of recovery is monitored by echocardiography (with measurement of left ventricular dimensions, posterior and septal wall thickness in systole
and diastole, left ventricular long axis function, aortic
and mitral valve opening and closing). These
measurements are then repeated (on heparin) with the
device switched off for 5 then 10 then 15 min. If this is
well tolerated, the echo is repeated after a ‘6 min
walk’ with the device switched off and the distance
covered is measured. If a 6 min walk distance of
300 m is achieved with no deterioration in echo
parameters, exercise capacity with measurement of
VO2 max is determined with the device off after an
appropriate period of rest (>6 h). MUGA scans are
performed (for left ventricular and right ventricular
ejection fractions and response to exercise) if there is
echocardiographic evidence of maintained left ventricular function off the machine for 15 min. Patients
also undergo right and left heart catheterization
(including left and right heart pressures, cardiac
output with the device on and off, left ventricular
angiography and left ventricular biopsies). Myocardial biopsies taken at cardiac catheterization
are examined by light microscopy and analysis is
performed to investigate the molecular mechanisms
that may be involved in remodelling and reverse
remodelling using quantitative real time polymerase
chain reaction, Western blotting and immunocytochemistry. Myocytes are isolated from left ventricular
core tissue at the time of implantation and from
biopsies taken during follow-up. Single cells are
prepared for size and force–frequency contraction
patterns and the change with offloading is studied.
Explantation of the device is considered if, with the
device off, ventricular dimensions are normalized,
ejection fraction is d45%, left ventricular enddiastolic pressure is c8 mmHg, cardiac index is more
than 2·8, and most importantly VO2 max is d20, and
VE/VCO2 <34[54].
Clinical experience
To date we have used the combination therapy in 17
patients. Of these, 14 were prospectively recruited,
while three were included from a previous programme of bridge to transplantation. At the time of
Eur Heart J, Vol. 22, issue 7, April 2001
80
70
60
50
40
30
(a)
100
80
60
40
20
0
20
0
5
10
15
20
25
Months post LVAD
200
400
600
800
Days post implant
Figure 5 Left ventricular ejection fraction (off pump)
before and after left ventricular assist device insertion and
the combined Harefield regime.
insertion of the device (Thermocardiosystems vented
electric Heart Mate I). All patients were in class IV of
NYHA classification, with a deteriorating haemodynamic state and varying degrees of end stage organ
failure, precipitated by the low cardiac output and
thought to be reversible. All patients had essentially
normal coronaries, and were on inotropic support,
and/or intra-aortic balloon counterpulsation. There
were three peri-operative deaths due to multi-organ
failure, and one late from infection. The remaining
patients have been followed-up for periods ranging
from 1–30 months, and all are clinically well. Of the
12 patients who were followed up for more than
2 months, all showed evidence of improved cardiac
function without the support of the left ventricular
assist device (Fig. 5). This was accompanied by
consistent diminution in left ventricular volumes and
improvement in exercise capacity. Four patients
underwent successful explantation of the device and
remained in class I NYHA for periods of 1–9 months.
One patient, who had to have the device explanted
before instituting the clenbuterol therapy, has a
dilated ventricle but no exercise limitation and no
clinical evidence of failure. The remaining patients
have normal left ventricular dimensions. Serial examination of blood and myocardial biopsies showed
progressive ‘normalization’ of the neurohumeral, cellular, molecular and functional changes (Figs 1–6)
known to be present in end-stage heart failure and
malfunctioning donor hearts with acute heart
failure[55,56].
Conclusion
A strategy of combined mechanical and pharmacological therapy of end-stage heart failure appears to
Eur Heart J, Vol. 22, issue 7, April 2001
120
–1
0
Serum interleukin 6 (pg.ml )
10
120
–1
Serum interleukin 6 (pg.ml )
M. H. Yacoub
(b)
100
80
60
40
20
0
0
5
10
15
20
25
30
Months post LVAD
Figure 6 Changes in serum interluekin 6 following left
ventricular assist device (LVAD) and pharmacological
therapy in two patients a & b.
150
Relative RNA abundance
ANP and BNP vs 18S
Ejection fraction (%) after exercise off pump
538
125
100
75
50
25
0
Implant
Explant
(25 month)
Figure 7 Relative expression of atrial (* - - - *) and
brain ( - - - ) natriuretic peptide) after insertion of a
left ventricular assist device.
result in fairly consistent ‘normalization’ of cardiac
structure and function. Further studies are required
to determine the longer term efficacy of this strategy
and elucidate further the concepts of ‘reverse
remodelling’ and ‘physiological hypertrophy’. It is
hoped that this will contribute to the management of
Clinical Perspective
these patients and possibly identify new targets for
therapy of heart failure.
M. H. YACOUB
Heart Science Centre,
Royal Brompton and Harefield Hospital,
Harefield, Middlesex, U.K.
The author gratefully acknowledges the contribution of
members of the LVAD research group for data included in this
article. These include Drs Patrick Tansley, Emma Birks, Chris
Bowles, Maren Koban, Cesare Terracciano, Virginia Owen,
Rahat Warraich and Paul Barton.
This work was supported by the Harefield Research Foundation,
the Royal Brompton and Harefield Charitable Trustees, the British
Heart Foundation and Thermocardiosystems Inc.
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