Review Article

Medical Progress

1522

November 19, 1998

The New Engl and Jour nal of Medi ci ne

I

MPLANTABLE

L

EFT

V

ENTRICULAR


A

SSIST

D

EVICES

D

ANIEL

J. G

OLDSTEIN

, M.D., M

EHMET

C. O

Z

, M.D.,

AND

E

RIC

A. R

OSE

, M.D.

From the Department of Surgery, Division of Cardiothoracic Surgery,
ColumbiaPresbyterian Medical Center, College of Physicians and Sur-
geons, Columbia University, New York. Address reprint requests to Dr.
Rose at the Department of Surgery, Milstein Hospital, 177 Fort Washing-
ton Ave., New York, NY 10032.
1998, Massachusetts Medical Society.

ONGESTIVE heart failure affects about 1 per-
cent of adults in the United States

1

and is a
contributing factor in over 250,000 deaths
annually.

2

It is diagnosed in 400,000 Americans
each year

3

and is the primary diagnosis for over
900,000 hospitalizations per year.

4

In 1990 the age-adjusted death rate from conges-
tive heart failure was 106.4 per 100,000,

5

more than
that from breast cancer and the acquired immuno-
deficiency syndrome combined.

6,7

The median sur-
vival after diagnosis is 1.7 years in men and 3.2 years
in women, with a 5-year survival rate of less than 50
percent.

8

Even though medical therapies have im-
proved survival and the quality of life,

9,10

recent es-
timates indicate that nearly 60,000 patients annually
in the United States could benefit from heart trans-
plantation or long-term mechanical support.

11

The introduction of cyclosporine in the 1980s

12

established heart transplantation as the most effec-
tive therapy for end-stage heart disease, including
congestive heart failure, with 10-year survival rates
after transplantation approaching 50 percent.

13

The
condition of an increasing number of patients dete-
riorates, however, to the point that they require con-
tinuous intravenous inotropic support until a suit-
able donor heart becomes available and up to 30
percent die before that occurs.

14

In 1996, 10.4 per-
cent of patients awaiting heart transplantation died
before receiving a heart.

15

Efforts aimed at increas-
ing the supply of donor organs

16

currently about
2500 hearts annually

17

have failed to ameliorate
the shortage, underscoring the crucial need for al-
ternatives to cardiac allotransplantation. Mechanical
C

support by means of ventricular assist devices is at
present the most promising alternative.

VENTRICULAR ASSIST DEVICES

Ventricular assist devices are mechanical pumps
that take over the function of the damaged ventricle
and restore normal hemodynamics and end-organ
blood flow. These devices are useful in two groups
of patients. The first group consists of patients who
require ventricular assistance to allow the heart to
rest and recover its function. Under these circum-
stances, it is critical to obtain complete drainage of
the ventricle in order to unload the ventricle, dimin-
ish myocardial work, and maximize subendocardial
perfusion.

18

Most often, these are patients with post-
cardiotomy shock. The second group consists of pa-
tients with myocardial infarction, acute myocarditis,
or end-stage heart disease who are not expected to
recover adequate cardiac function and who require
mechanical support as a bridge to transplantation.

19-22

The available ventricular assist devices include ex-
tracorporeal membrane oxygenation, univentricular
and biventricular extracorporeal nonpulsatile devic-
es, extracorporeal and implantable pulsatile devices,
and the total artificial heart (Table 1). Although
most of these devices require the patient to be con-
nected to cumbersome extracorporeal drive systems,
miniaturization of control and power-supply com-
ponents has resulted in the development of wearable
left ventricular assist devices. This latest generation
of devices makes possible patients rehabilitation,
unrestricted mobility, discharge home, and return to
work.

23

The increasing duration of implantation now
raises the critical question of the suitability of im-
plantable left ventricular assist devices for long-term
use,

24

for which they may have some advantages over
heart transplantation. These include the possibility
of earlier intervention and rehabilitation and the
avoidance of the risks associated with immunosup-
pression and of rejection. Most important, the de-
vices could be produced in the quantities required
to treat all the patients who might otherwise die be-
fore receiving a transplanted heart. This review will
focus on the development of implantable left ven-
tricular assist devices.

A HISTORICAL PERSPECTIVE

In 1964 the National Heart, Lung, and Blood In-
stitute began to sponsor the development of me-
chanical devices for short- and long-term circulatory
support, including a total artificial heart (Table 2).

25

Ten years later, support focused on the development
of electrically powered, totally implantable devices,
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MEDI CAL PROGRESS

Vol ume 339 Number 21

1523

largely because of concern that pneumatically acti-
vated devices could not be sufficiently miniaturized
to provide a suitable quality of life. At the time, the
available devices required patients to be tethered to
bulky external power sources that restricted mobility
and independence.
The 1980s marked the first implantation of a pneu-
matic total artificial heart (Jarvik-7-100) by DeVries
et al.

26

Shortly thereafter, Copeland et al. described
a long-term survivor who had received a total artifi-
cial heart as a bridge to cardiac transplantation.

27

The
initial enthusiasm for implantation of the total arti-
ficial heart soon faltered; the high incidence of throm-
boembolic events

28

and severe infections

29,30

and the
low survival rates culminated in 1991 with a mora-
torium on the use of the Jarvik heart in the United
States.

28

By then, a multicenter clinical evaluation of left
ventricular assist devices as a bridge to transplanta-
tion had demonstrated a 65 percent rate of survival
to transplantation, as compared with 50 percent for
medically treated patients.

21

On the basis of this and
other studies,

31,32

the Food and Drug Administra-
tion (FDA) approved the use of a left ventricular as-
sist device with an external power source as a bridge
to transplantation in 1994.
In this decade, technological advances in the de-
sign of left ventricular assist devices, biomaterials,
and miniaturization have eliminated bulky external

*The intraaortic balloon pump is not included here, because it does not produce its own stroke volume.
Centrifugal-flow pumps and extracorporeal membrane oxygenation are included in this category.
The PierceDonachy device (Thoratec Laboratories, Berkeley, Calif.) and the Abiomed device (Abiomed, Danvers, Mass.) are included in this category.
The Novacor left ventricular assist system (Baxter Healthcare, Oakland, Calif.) and the Heartmate left ventricular assist device (ThermoCardiosystems,
Woburn, Mass.) are included in this category.
The Cardiowest artificial heart (Cardiowest, Tucson, Ariz.) and the Penn State pneumatic artificial heart are included in this category.

T

ABLE

1.

C

LINICALLY

T

ESTED

M

ECHANICAL

P

UMPS



FOR

C

ARDIAC

S

UPPORT

.

P

UMP

T

YPE

* A

DVANTAGES

D

ISADVANTAGES

I

NDICATIONS

Extracorporeal nonpulsatile Simple cannulation, inexpensive,
univentricular or biventricular,
readily available, extensive clini-
cal experience
Short-term support, requires continuous
availability of trained bedside personnel,
systemic anticoagulant therapy needed,
bleeding and thromboembolism possible,
patient necessarily bedridden, no potential
for rehabilitation
Postcardiotomy ventricular dysfunction,
neonatal respiratory failure (extracor-
poreal membrane oxygenation)
Extracorporeal pulsatile Univentricular or biventricular Short-term support, systemic anticoagulant
therapy needed, patient usually bedridden,
bleeding and thromboembolism possible,
limited potential for rehabilitation
Postcardiotomy ventricular dysfunction,
right-sided heart failure after left ven-
tricular assist device implantation,
bridge to transplantation
Implantable pulsatile Potential for outpatient and long-
term support, excellent poten-
tial for rehabilitation
Expensive, univentricular support, abdomi-
nal placement required, infection possible,
mechanical failure possible, bleeding and
thromboembolism possible
Bridge to transplantation, bridge to
recovery, potential long-term use
Total artificial heart Biventricular support, orthotopic
placement
Not FDA-approved, bleeding and thrombo-
embolism possible, bulky external console,
systemic anticoagulant therapy needed,
infection possible, mechanical failure
possible, expensive
Biventricular failure, bridge to trans-
plantation

T

ABLE

2.

L

ANDMARK

E

VENTS
IN



THE

D

EVELOPMENT



OF

V

ENTRICULAR

A

SSIST

D

EVICES

.

Y

EAR

E

VENT

1954 Development of the cardiopulmonary-bypass machine
1964 Chartering of the Artificial Heart Program by the National
Heart, Lung, and Blood Institute
1966 First use of a pneumatic device as a bridge to recovery
1967 First human heart transplantation
1969 First successful use of a pneumatic total artificial heart as a
bridge to transplantation
1970s Development of a variety of extracorporeal and implantable
pneumatic ventricular assist devices
1974 Redirection of the efforts of the Artificial Heart Program
toward the development of implantable devices
1984 First implantation of a total artificial heart as a permanent
device
1985 Multicenter evaluation of left ventricular assist devices as a
bridge to transplantation
1991 Moratorium on the use of the total artificial heart
1993 FDA approval of a New Investigational Device exemption for
a total artificial heart
1994 FDA approval of a left ventricular assist device as a bridge to
transplantation
1994 First use of a wearable left ventricular assist device
1996
present
Recruitment of patients for a randomized trial comparing
wearable left ventricular assist device with medical therapy
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1524

November 19, 1998

The New Engl and Jour nal of Medi ci ne

consoles, and wearable systems have performed re-
markably well in patients awaiting transplantation.
With existing devices, 91 percent of patients with se-
vere congestive heart failure can be discharged from
the hospital, and 74 percent survive to undergo trans-
plantation.

33

The goal of fully implantable systems
has yet to be attained, however, largely because of
problems of reliability.

WEARABLE LEFT VENTRICULAR ASSIST
DEVICES

Technological advances in miniaturization have
resulted in the development of electrically powered,
wearable left ventricular assist devices that allow pa-
tients to leave the hospital and resume an independ-
ent existence (Fig. 1). The current state of the art is
represented by two systems, the ThermoCardiosys-
tems Heartmate 1205 VE device (ThermoCardio-
systems, Woburn, Mass.) and the Novacor N100 left
ventricular assist system (Baxter Healthcare, Oak-
land, Calif.). Both devices are implanted through a
median sternotomy with an inflow cannula inserted
into the left ventricular apex and an outflow tube
anastomosed to the ascending aorta. The pumping
chamber is placed within the abdominal wall.

34

Both devices can be operated either in a fixed-rate
mode or, more often, in an automatic mode that
more closely resembles normal physiologic condi-
tions.

35

In the automatic mode, the device ejects
when the pump is 90 percent full or when it senses
a decreased rate of filling. As the patients activity in-
creases, the pump fills faster and the rate (or stroke
volume) automatically increases, resulting in an in-
crease in pump output. With a decrease in activity,

Figure 1.

A Wearable Left Ventricular Assist Device and Its Components.
The inflow cannula is inserted into the apex of the left ventricle, and the outflow cannula is anasto-
mosed to the ascending aorta. Blood returns from the lungs to the left side of the heart and exits
through the left ventricular apex and across an inflow valve into the pumping chamber. Blood is then
actively pumped through an outflow valve into the ascending aorta. The pumping chamber is placed
within the abdominal wall. One transcutaneous line carries the electrical cable and air vent to the bat-
tery pack and electronic controls, which are worn on a shoulder holster or belt.
Diaphragm
Aorta
External
battery pack
and controls
Outflow
External
wires
Dermaport
access device
Heartmate
blood pump
Left
ventricle
Drive line
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MEDI CAL PROGRESS

Vol ume 339 Number 21

1525

pump filling and output decrease. Because the aortic
valve rarely opens when the heart is being supported
by a left ventricular assist device, pump output is
synonymous with cardiac output.
Both devices can deliver a cardiac output of up to
10 liters per minute and have similar stroke volumes
and maximal rates. The Heartmate system uses tex-
tured biologic surfaces (Fig. 2A). Blood is expelled
from the device by a single pusher plate activated by
a rotary electric motor. The Novacor device (Fig. 2B)
uses smooth polyurethane biologic surfaces and re-
quires that the patient receive long-term warfarin
therapy. Electromagnetically activated double push-
er plates power the system.
A single drive line containing the electrical cable
and the atmospheric air vent leads transcutaneously
from the implanted pump to the outside (Fig. 1).
The line is covered with polyester velour that pro-
motes tissue bonding at the skin, firmly anchoring
the line to the skin and reducing the risk of infec-
tion. Both devices are powered by two rechargeable
batteries that provide four to six hours of charge and
are usually worn in a shoulder holster, vest, or belt.
The wearable electrical devices currently available
have external backup mechanisms to continue sup-
port without the need for reoperation in case of fail-
ure of the device.

24

If the device should fail, the na-
tive heart would usually be able to provide systemic
support until the device could be examined. Because
the electronic control unit is outside the body, it can
easily be repaired should failure of the software,
chip, or electronics occur. Finally, if the motor de-
vice fails, the single-pusher-plate device can be pneu-
matically activated with a hand-held portable pump.
Although much attention has focused on the de-
velopment of esthetically appealing, fully implantable

Figure 2.

Two Left Ventricular Assist Devices.
Panel A shows the pumping chamber of the opened Thermo-
Cardiosystems device. The textured polyurethane diaphragm
covered by a thin neointimal lining is shown on the left, and
the sintered titanium housing is shown on the right. Panel B
shows the unencapsulated pump-drive unit of the Novacor left
ventricular assist system.

A
B
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1526

November 19, 1998

The New Engl and Jour nal of Medi ci ne

mechanical devices, a number of obstacles currently
preclude their clinical use. With all pulsatile systems,
a compliance chamber is necessary to compensate for
air displacement.

36

Efforts to develop an implantable
compliance chamber to avoid the need for external
venting have met with recurrent technical problems
relating to buildup of fibrous tissue and accumulation
of water in the chamber and escape of gas from it.

LEFT VENTRICULAR ASSIST DEVICES
AS A BRIDGE TO TRANSPLANTATION

Selection of Patients

Selection is a crucial consideration that deter-
mines the ultimate outcome of patients who receive
a left ventricular assist device. In general, patients
who have been selected to receive left ventricular as-

Figure 3.

Scheme for Selection of Patients with Acute Cardiac Disease or Congestive Heart Failure for Implantation of Left Ventric-
ular Assist Devices.
Adequate
support?
No
No
No
Recovery?
Yes
Transplantation
No
No
Yes
Adequate right
ventricular function?
Yes
Transplantation
Previously healthy patient
Intraaortic balloon pump
Short-term left
ventricular assist device
Patient with congestive
heart failure
Acute hemodynamic
deterioration
Optimize clinical status,
rehabilitation
Bridge to transplantation
or to recovery
Inotropes, inhaled nitric
oxide, short-term right
ventricular assist device
Donor organ
available?
Donor organ
available?
Implantable
left ventricular
assist device
Intraaortic balloon pump
if patient has coronary
artery disease
Myocardial infarction,
inability to wean from
cardiopulmonary bypass,
or acute myocarditis
Yes
Weaning
Yes
Weaning
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MEDI CAL PROGRESS

Vol ume 339 Number 21

1527

sist devices have end-stage heart disease without ir-
reversible end-organ failure. For patients who are
too ill to undergo heart transplantation, such as those
who cannot be weaned from cardiopulmonary by-
pass, use of a short-term extracorporeal left ventric-
ular assist device is a first-line therapy (Table 1). For
patients who are suitable candidates to receive a
heart transplant but are unlikely to survive the three-
to-four-month wait currently required before trans-
plantation, left ventricular assist devices are an effec-
tive bridge to transplantation. The Food and Drug
Administration has recently approved the marketing
of both the Heartmate system and the Novacor de-
vice for use as bridges to transplantation. Bridging
is particularly valuable for large patients with type O
blood and for patients with a positive panel-reac-
tiveantibody titer for whom prospective cross-
matching is required.

37

Although left ventricular as-
sist devices have not yet been used in patients who
are not considered candidates for heart transplanta-
tion, such as those with severe diabetes mellitus or
advanced age, left ventricular assist devices may ulti-
mately be the preferred therapy. A commonly used
scheme for the selection of patients for implantation
of left ventricular assist devices is shown in Figure 3.

Cardiac Factors Affecting Selection

Valvular Heart Disease

Patients with preexisting mitral stenosis or aortic
regurgitation may require correction of the valvu-
lopathy before implantation of the device (Fig. 4).

Coronary Artery Disease

Patients with inoperable coronary artery disease
sometimes continue to have angina without adverse
hemodynamic effects while being supported by a left
ventricular assist device. However, right ventricular
ischemia and myocardial injury soon after implanta-

Figure 4.

Physiology of Blood Flow through a Left Ventricular Assist Device (LVAD) in Patients with Valvular Heart Disease.
Mitral stenosis, if severe, will limit filling of the device and should be corrected. Mitral regurgitation does not limit the proper func-
tioning of the device; complete unloading of the left ventricle after placement of the device results in complete afterload reduction
of the left ventricle, eliminating mitral regurgitation. Mild aortic stenosis in the absence of insufficiency is not a contraindication to
placement of a left ventricular assist device. If aortic insufficiency is present, blood pumped into the aortic root by the device will
flow backward across the incompetent aortic valve (aortic regurgitation), thereby decreasing net forward flow and compromising
end-organ perfusion. Even mild-to-moderate aortic insufficiency can become severe with institution of support from a left ventric-
ular assist device, because the usually elevated left ventricular end-diastolic pressure will be reduced to nearly zero, whereas the
base-line low systemic pressure will be elevated. Wide black bars indicate stenosis. PA denotes pulmonary artery, RA right atrium,
RV right ventricle, LA left atrium, and LV left ventricle.
LA
Mitral
stenosis
Aorta
LV
LA
Aortic
stenosis
Aorta
LV
LA
Aortic
regurgitation
Mitral
regurgitation
Aorta
LV
LA
Aorta
LV
No valvular
disease
LA
Aorta
LVAD
LVAD LVAD
LVAD LVAD
LV
RA
RV
PA
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1528

November 19, 1998

The New Engl and Jour nal of Medi ci ne

tion of the device can cause right-sided heart failure,
resulting in decreased flow to the left ventricular as-
sist device. In patients who have had coronary by-
pass surgery, efforts are made to preserve patent
grafts in order to reduce the risk of perioperative
right-sided ischemia and arrhythmias. On occasion,
surgery is performed to bypass lesions of the right
coronary artery at the time of implantation of the
device, in an attempt to optimize perioperative right-
sided heart function.

Arrhythmias

Atrial and ventricular arrhythmias, which are com-
mon in patients with cardiomyopathies, continue to
occur after implantation of the device.

38

Atrial fibril-
lation hinders right ventricular filling but is reason-
ably well tolerated in recipients of left ventricular as-
sist devices.
Severe ventricular arrhythmias were previously be-
lieved to be a contraindication to univentricular sup-
port. Recent experience, however, has revealed no se-
rious hemodynamic compromise in patients in whom
these arrhythmias develop in the late postoperative
period. In a 1994 study,

39

9 of 21 recipients of left
ventricular assist devices had severe ventricular ar-
rhythmias 0 to 186 days after implantation of the de-
vice. The mean arterial and central venous pressures
were not changed by the arrhythmias. The flow
through the device decreased by an average of 1.4 li-
ters per minute at the onset of the arrhythmia but
returned to normal after cardioversion. No syncope,
thromboembolic events, or major end-organ dys-
function occurred. During ventricular fibrillation and
in the absence of pulmonary hypertension, recipients
of left ventricular assist devices tolerate the equiva-
lent of a Fontan (systemic vein to pulmonary artery)
circulation. Nonetheless, early electrical or pharma-
cologic cardioversion is warranted to avoid throm-
bus formation and improve exercise tolerance.

Congenital Defects

Intracardiac septal defects should be repaired at
the time of implantation of the device to avoid the
right-to-left shunt and subsequent oxygen desatura-
tion that would be created by the sudden reduction
in left filling pressures.

40

Extracardiac Factors Affecting Selection

Patients undergoing implantation of a device as a
bridge to heart transplantation often have end-organ
dysfunction related to long-term cardiac insufficien-
cy. They are usually chronically debilitated and must
withstand the rigors of two operations (device im-
plantation and heart transplantation), with the risks
entailed by immunosuppressive therapy after the sec-
ond operation. Functional compromise of end-organs
must be carefully considered in selecting candidates
for implantation of left ventricular assist devices.
The presence of irreversible major neurologic def-
icits is a contraindication to implantation of a left
ventricular assist device and heart transplantation.
Severe obstructive or restrictive pulmonary disease is
also a contraindication, because these patients often
have oxygen desaturation in the perioperative period
that can result in hypoxic pulmonary vasoconstric-
tion and right-sided heart failure. Decreased pulmo-
nary diffusion capacity, on the other hand, is com-
mon in patients with heart failure

41

(especially those
receiving amiodarone

42

) and is not considered a con-
traindication. Moderately elevated pulmonary vascu-
lar resistance is also commonly encountered

43

and
does not preclude successful implantation of a de-
vice, particularly if the central venous pressure is low.
Although dependence on hemodialysis is a con-
traindication to implantation of a device, moderate
renal insufficiency due to low cardiac output does
not preclude it. In patients with such renal insuffi-
ciency, renal function improves as hemodynamics
improve and the need for vasoconstricting drugs is
reduced. Continuous venovenous hemofiltration is
often necessary in the postoperative period to facili-
tate fluid management in these patients.
Preoperative hepatic insufficiency manifested by
elevated prothrombin times is present in most pa-
tients with right-sided heart failure. Perioperative
bleeding, to which these patients are prone, will fur-
ther exacerbate right-sided heart failure and lead to
increasing hepatic congestion and coagulopathy. Any
coagulopathy present before surgery should be cor-
rected aggressively. Persistence of a prothrombin
time greater than 16 seconds usually contraindicates
placement of a device.

44

Arterial and aortoiliac dis-
ease of the lower extremities complicates transfemo-
ral institution of cardiopulmonary bypass, which is
sometimes necessary at the time of removal of the
device.
Additional factors that may complicate placement
of a device and compromise survival include long-
term glucocorticoid therapy and small body-surface
area (less than 1.5 m

2

). The complication due to
small body-surface area results from the need to im-
plant the pumping chamber of the device beneath
the abdominal wall without causing excessive dis-
ruptive force on the wound.
Finally, the development of long-term implantable
devices that allow patients to be discharged to their
homes has imposed the need to assess a patients
ability to manage the device before implantation can
be offered. The presence of a constant companion,
though desirable, is no longer required.

Interactions between the Patient and the Device

Left ventricular assist devices used as a bridge to
transplantation restore near-normal resting hemody-
namics and reasonable exercise tolerance. In a recent
assessment of submaximal exercise capacity, patients
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MEDI CAL PROGRESS

Vol ume 339 Number 21

1529

with left ventricular assist devices performed signifi-
cantly better on a six-minute walk testing than do-
butamine-dependent patients and similarly to patients
with mild heart failure. The mean (SE) distance
covered was 476.1123.1 m (1562404 ft) for 14
patients with left ventricular assist devices, 289.0
73.5 m (948241 ft) for 20 patients receiving do-
butamine, and 413.984.7 m (1358278 ft) for 14
patients with heart failure (P<0.01).

45

Similarly, oxy-
gen consumption was also greater in the patients
with left ventricular assist devices than in the other
two groups (16.36.5 ml per kilogram per minute
for patients with left ventricular assist devices, 9.8
4.8 ml per kilogram per minute for patients receiv-
ing dobutamine, and 11.22.0 ml per kilogram per
minute for patients with heart failure; P<0.05). In
patients studied five months after the institution of
support with a left ventricular assist device, peak oxy-
gen consumption was significantly better than that
of patients with New York Heart Association class
III heart failure.

46

In some patients, the peak oxygen
consumption was higher than would be predicted
from maximal pump flow, suggesting the recovery of
native heart function.
The mechanical unloading afforded by the left
ventricular assist device results in attenuation of the
myocardial histologic abnormalities caused by chron-
ic heart failure,

47

including normalization of fiber
orientation,

48

regression of myocyte hypertrophy,

49

and reduction in myocyte wavy fibers and con-
traction-band necrosis.

50
Prolonged left ventricular
unloading reverses ventricular dilatation, as demon-
strated by an improvement in the end-diastolic pres-
surevolume relation.
51
Long-term support with a
left ventricular assist device improves the efficiency
of myocardial mitochondria
52
and results in a re-
duction in the neuroendocrine perturbations that
accompany congestive heart failure (including ab-
normalities in plasma renin activity and plasma con-
centrations of angiotensin II, epinephrine, norepi-
nephrine, and arginine vasopressin).
53,54
Many centers
have reported patients with left ventricular assist de-
vices whose myocardial function improved enough
to allow removal of the device, rather than the pre-
viously necessary heart transplantation, a scenario
now termed a bridge to myocardial recovery.
51,55
Another valuable lesson learned from the experi-
ence with left ventricular assist devices as a bridge to
transplantation is that the use of porcine inflow and
outflow valves and a wandering-vortex blood-flow
pattern can reduce the risk of thromboembolism.
56
Increasing evidence points to interactions between
the host (patient) and the graft (the surface of the
left ventricular assist device) that maintain a delicate
balance between activated procoagulant and fibrino-
lytic cascades. A recent study documented the pres-
ence of sustained thrombin generation and fibrinol-
ysis in patients with left ventricular assist devices,
despite their normal values on routine coagulation
tests.
57
The low incidence of thromboembolic events
in recipients of textured-surface left ventricular assist
devices suggests that this low-grade disseminated in-
travascular coagulopathy reduces the risk of clinically
important thromboembolism. Absorption of tissue
macrophages that express tissue factor by the surface
of the device may be the trigger that generates this
systemic procoagulant state.
58
Patients Adaptation to the Device
Surgical intervention should not only restore nor-
mal resting hemodynamics but also provide the pa-
tient with substantial improvement in the quality of
life. Debilitated recipients of left ventricular assist
devices require weeks of aggressive nutritional sup-
port and rehabilitation to restore muscle mass and
strength. Early in the postoperative period, patients
begin a rehabilitation program that encourages pro-
gressive mobilization from walking to treadmill ex-
ercise to cycling. These programs have promoted
optimal physical recovery before heart transplanta-
tion,
59
and in most instances they facilitate the pa-
tients discharge home. Furthermore, the autonomy
gained unquestionably increases the patients emo-
tional well-being.
60,61
After implantation of a left ventricular assist de-
vice, patients can often return to work and engage
in other activities, including gardening, dancing, and
driving.
23
Of 24 patients treated by us who were dis-
charged home on mechanical support, 6 returned
to school and 5 returned to work. Only activities
that would result in the submersion of percutaneous
lines (such as swimming) are proscribed, although
showering is possible with special precautions for
the air vent.
COMPLICATIONS
Bleeding, right-sided heart failure, air embolism,
and progressive multisystem organ failure are the
most common causes of early morbidity and mortal-
ity after placement of a left ventricular assist device.
The most common complications in the late postop-
erative period are infection, thromboembolism, and
failure of the device.
Bleeding
Hemorrhage is the most common complication
associated with placement of a left ventricular assist
device. In the early experience, about 50 percent of
patients required reoperation for bleeding,
62
but the
risk of major hemorrhage has decreased to about 30
percent with the use of the serine protease inhibitor
aprotinin.
63
Perioperative hemorrhage can have many
causes, including preoperative coagulopathy due to
hepatic dysfunction, poor nutritional status, and an-
tibiotic therapy; cardiopulmonary-bypassinduced
thrombocytopenia and platelet dysfunction; and the
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1530 November 19, 1998
The New Engl and Jour nal of Medi ci ne
extensive nature of the surgery, which requires me-
dian sternotomy, cardiac mobilization (often in pa-
tients who have had previous cardiac surgery), and
extensive dissection of the abdominal wall to create
a pocket for the pump.
Right-Sided Heart Failure
Hemodynamic stability can be attained with iso-
lated mechanical left ventricular support in more
than 90 percent of patients,
64
even in those with
substantial right ventricular dysfunction, if there is
effective replacement of left-sided heart function and
treatment of pulmonary hypertension.
Historically, right-sided heart failure of sufficient
severity to warrant the use of a right ventricular as-
sist device occurred in nearly 20 percent of recipi-
ents of left ventricular assist devices
21
and was the
leading cause of perioperative death for patients un-
dergoing placement of a left ventricular assist device.
62
More recently, improved perioperative management,
including the use of inhaled nitric oxide,
65,66
has re-
duced the need for placement of a right ventricular
assist device. The need was reduced from 15 percent
(8 of 55 patients) to 7 percent (3 of 45 patients)
after the introduction of nitric oxide at our insti-
tution.
67
Right-sided heart failure is usually associated with
perioperative hemorrhage and the need for blood
transfusion.
63
Right-sided heart failure rarely devel-
ops in patients who do not have major bleeding in the
perioperative period. It may be cytokine-mediated;
hemorrhage and resuscitation increase the produc-
tion of several cytokines, including interleukin-1b,
interleukin-6, and interleukin-10, as well as tumor
necrosis factor a.
68
Tumor necrosis factor a can in-
duce pulmonary hypertension,
69
and its effect may
be mediated by platelet-activating factor,
70,71
a po-
tent vasoconstrictor of the pulmonary circulation.
72,73
Thromboembolism
Historically, thromboembolic events occurred in
about 20 percent of patients receiving a left or right
ventricular assist device.
33
In a more recent multi-
center study,
74
the total thromboembolic event rate
was 0.01 per patient-month of device use among
223 patients supported with a Heartmate left ven-
tricular assist device over a total support time of 531
patient-months. This low incidence has been attrib-
uted to the use of textured blood-contacting surfac-
es.
57,58,74
Because of the low incidence of thrombo-
embolic events, most patients receiving this device
do not require long-term anticoagulant therapy with
warfarin but instead receive only an antiplatelet drug
such as aspirin. Intraoperative air embolism occurs
rarely because the devices are cleared of air and the
left ventricle is filled before the device is activated.
Prospective transcranial Doppler examinations have
documented asymptomatic cerebral microemboli in
34 to 67 percent of recipients of left ventricular as-
sist devices.
75,76
Infection
Recipients of left ventricular assist devices are prone
to nosocomial and device-related infections. The
former occur as a result of the patients prolonged
hospitalization, immobilization, endotracheal intu-
bation, suboptimal nutritional status, and need for
multiple intravascular and bladder catheters.
77,78
The
most common infections in recipients of the device
those related to the drive line remain confined
to the exit site and are manageable with local wound
care and antibiotics. Infections in the abdominal-
wall pocket holding the device require more aggres-
sive treatment, including open drainage, dbridement,
and rerouting of the drive line through a fresh exit
site. On very rare occasions, supervening sepsis ne-
cessitates replacement of the device.
77
Fortunately,
these infections do not preclude heart transplanta-
tion.
79,80
According to a review of more than 2000
patients in 73 centers worldwide,
34
clinically impor-
tant infections occurred in 25 percent of recipients
of left ventricular assist devices.
Device Malfunction
Anecdotal reports of device malfunction have ap-
peared.
81
Among 14 outpatients with left ventricular
assist devices in one series, there were 29 controller
malfunctions during 1640 days of support.
23
None
of the malfunctions threatened the ability of the de-
vice to provide adequate blood flow, and all were
easily repairable.
Other Complications
Hemolysis has been described in patients with
centrifugal- and axial-flow left ventricular assist de-
vices,
82
but it has not been a clinical problem in pa-
tients with implantable left ventricular assist devices.
On occasion, placement of a left ventricular assist
device has been associated with transient early sati-
ety and inability to tolerate oral intake.
83
FUTURE DIRECTIONS
Long viewed as an unattainable goal, long-term
mechanical support as a useful therapy for patients
with end-stage heart disease seems inevitable; these
patients will probably be in a situation similar to that
of patients with end-stage renal disease. Patients
with heart failure that progresses to end-stage heart
disease may eventually undergo placement of a left
ventricular assist device, with the option of indefi-
nite mechanical support or heart transplantation in
the event that a donor organ becomes available.
The bridge to recovery is a theoretically attractive
application for this technology. There is increasing
understanding of the mechanisms that lead to cardi-
ac remodeling and recovery of left ventricular func-
Downloaded from www.nejm.org on January 24, 2008 . Copyright 1998 Massachusetts Medical Society. All rights reserved.
MEDI CAL PROGRESS
Vol ume 339 Number 21 1531
tion
51,55
and of the factors that predict the ability of
a patient to function successfully after the removal of
a left ventricular assist device, without receiving a
heart transplant. Several methods have been pro-
posed to predict successful weaning from and re-
moval of a left ventricular assist device,
55,84-86
includ-
ing exercise testing while flow through the device is
reduced substantially. Although successful explanta-
tion of a device without heart transplantation re-
mains desirable, the experience in such cases is anec-
dotal,
57,87
and the long-term function and survival of
the patients are unknown.
The increased use of mechanical support in pa-
tients with end-stage heart disease may improve the
outcome of heart transplantation, because the he-
modynamic and clinical benefits of mechanical as-
sistance can convert high-risk, terminally ill patients
into stable, reconditioned heart-transplant recipients.
Because these patients can return to their homes
while awaiting transplantation, the need for and
costs of hospitalization should be reduced. More im-
portant, survival after transplantation may be higher
as healthier patients undergo transplantation. We
know of at least 40 patients who have received me-
chanical support for more than 300 days, and a
growing number are returning to normal activities.
Modification of the devices to increase long-term
reliability and reduce infectious and thromboembol-
ic complications may be necessary before they can
be used widely. At present, three classes of device are
at advanced stages of preclinical development. One
is a new generation of pneumatic, direct mechanical
ventricular assist devices that are wrapped around
the heart and do not directly contact the blood. The
second consists of compact axial-flow pumps that do
not require a compliance chamber and are capable
of delivering a high cardiac output. The third is rep-
resented by the reapproved pneumatic total artificial
heart.
88
The artificial heart may have a role as a
bridge to transplantation for a subgroup of patients
with severe biventricular dysfunction and a fixed in-
crease in pulmonary vascular resistance in whom left
ventricular support may not be sufficient. Obligato-
ry systemic anticoagulant therapy, restricted mobili-
ty, and lack of experience with the long-term use of
the devices, however, limit their applicability as a
means of permanent mechanical support.
The future of mechanical support will probably be
shaped by the results of an ongoing study compar-
ing the use of a left ventricular device with medical
therapy
24
and by the forthcoming availability of small-
er, fully implantable devices.
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