Perspectives on Long Term Mechanical Circulatory Support for the Failing
Heart

; , Claude Lenfant M.D.

From: The National Heart, Lung and Blood Institute,
Bethesda, Maryland

Running Title: Mechanical Circulatory Support

Address for Reprints: Claude Lenfant, M.D.
Director, National Heart, Lung and Blood Institute
Bldg. 31, Room 5A52
Bethesda, MD 20892

Dr Derweuk: . 1 Lasse. ee
Msc
The National Heart, Lung, and Blood Institute (NHLBI) has a continuing
program of support for the development of mechanical circulatory support
systems. Started as the Artificial Heart Program in 1964, jit has
resulted in a number of significant advances, including the hollow fiber
membrane oxygenator and the intra-aortic balloon pump. Today, the primary
focus of the program is the development and testing of a fully
implantable, tether-free, left ventricular assist system (LVAS) intended
for long-term use in patients with severe, medically intractable, heart

failure.

The continued clinical need for, and progress toward, development of
implantable devices for circulatory support will be discussed. Important
clinical results will be noted and the NHLBI plan for clinical evaluation
of an implantable LVAS will be described. Implantable artificial hearts
to be used in the future will be briefly discussed. Of necessity, efforts
in the last 25 years have focused primarily on technical development. The
science has now matured to a point where evaluation of the safety and
efficacy of fully implantable systems can begin. Preliminary information
about the impact of these systems on quality of life will be a focus of

this evaluation.

Need. Heart failure is a worldwide problem. In the United States, alone,
3 million people suffer from congestive heart failure (CHF) (1). CHF
develops in 400,000 people each year and it is the most common hospital

discharge diagnosis in patients older than 65 (1). At a time when death
from heart disease is declining (2), the prevalence of CHF is increasing

(1).

Treatment. Symptomatic treatment of CHF involves the use of diuretics,
vasodilators and _ inotropes. The vasodilators have been shown to
favorably affect survival (3,4). Despite advances in medical treatment,
however, the prognosis remains bleak, with many patients progressing to a
point where their hearts are incapable of sustaining life (1). Cardiac
transplantation has become the treatment of choice for end-stage heart
failure with 5 year survival rates in the range of 50% (5). The number of
donor hearts available is , however, far less than the number of potential
recipients. It is estimated that a maximum of @ Botfsand donor hearts per
year are available compared with a need of 14,000 to 35,000 (6). A 1988
GAO) report on cardiac transplantation in the United States also provides
some insight regarding donor heart availability (7). During 1988, 1,529
transplants were performed, there were 929 patients on the waiting list,
and 297 of these have been waiting for 6 months or longer. Additionally,

515 patients died while awaiting a donor organ.

A potential solution to the problem of donor heart availability would be
advances in manipulation of the immune system that would permit
xenografting. Such advances do not appear likely in the near future, Cu an
OMtrrarr of Water Owe a VOL ull Yeerrerete. -

Because of a lack of alternative solutions, mechanical assistance for, or
replacement of, a patient’s heart may be an attractive therapeutic

alternative for patients for whom a donor organ is not available. It is

t
for this reason that the NHLBI has pursued research aimed at the
development of mechanical systems capable of supporting the failing

circulation.

Artificial Heart Program. The Artificial Heart Program of the NHLBI has
provided support over the years for research on circulatory support
systems. A number of developments have resulted including extracorporeal
systems for emergency cardiopulmonary bypass and left ventricular assist
systems (LVAS’s) for support of patients with post-cardiotomy ventricular

dysfunction or as a bridge to transplant.

The ultimate goal of this program is the development of a totally
implantable artificial heart. The attainment of this goal requires the
solution of many complex problems related to both biomaterials and
engineering design. The artificial heart program has utilized a step-by-
step approach of research into and evaluation of progressively more

sophisticated circulatory assist devices.

Devices. As the state-of-the-art advanced, devices in common use today
were developed. The intra-aortic balloon pump, for instance, was made
possible by the development of appropriate polymers and workable pneumatic
actuators. During the 1970’s, pneumatically powered ventricular assist
systems came into clinical use. These devices were developed as part of
the NHLBI research program (8,9). Several hundred have been used as a
bridge-to-transplant or support post-cardiotomy patients who could not

otherwise have been weaned from bypass. They have also been used, to a
lesser extent, to support patients following acute myocardial infarction.
The biomaterials program has importantly influenced the development of

materials used in these systems.

Bridge to Transplant. Because experience with ventricular assist devices
used as bridges to transplant has motivated the current focus of the
program discussed above, this use of LVAS’s deserves special mention.
The term "bridge-to-transplant" means that a mechanical device was used to
support a patient requiring hemodynamic support while awaiting a donor
heart. Most of the devices used have been pneumatically driven. About
40% of patients who received a mechanical device as a bridge were
discharged alive (10). In 1988 the discharge rate was 50%. Though these
data are uncontrolled, it is expected that without the placement of a
mechanical support device mortality would have approached 100%.
Experience with the current generation of temporary devices has led to the
expectation that long term, fully implantable systems might be developed

and this is now the primary objective of the Artificial Heart Program.

Long Term, Implantable Left Ventricular Assist System Development.
Figure 1 is a diagram of an implantable LVAS of the type under
development. In contrast to temporary devices, all of the major
components of the system are implantable with the exception of the
external batteries. Electrical power is transmitted across the intact
skin by a belt-skin transformer. An electronic control package modulates
the power to activate the blood pump. It also contains rechargeable

nickel-cadmium batteries for brief periods of operation independent of the
external battery pack. The blood pump is positioned in the muscle sheaths
of the left upper quadrant of the abdomen. The variable volume
compensator maintains a low resistance to passive filling of the pumping

chamber of the left ventricle. The system will deliver more than 10

liters per minute output at rates up to 180 beats per minute. The device

will be placed chronically in patients who might benefit from transplant

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program is being completed and human implants are expected to begin in

but who are unlikely to receive one. An engineering reliability testing
1991 following final animal testing.

Device Readiness Testing. The Device Readiness Testing program deserves
ecial mention because it is likely to become a prototype for reliability
testi of future (11,12) circulatory support systems. This program is
the first t esearch activity to assess and enhance the reliability of a
medical technology. It was undertaken to ensure the safety of the first
generation of implantable devices before the start of clinical studies.
The goal of the program is to demonstrate, with a high level of
confidence, an 80% reliability for two years of continuous operation.

Mock circulatory loops (Figure 2) were used to test the LVAS’s.

Operating characteristics were monitored 24 hours a day.

Although mock loops are useful for demonstrating engineering reliability,
they have certain limitations. For instance, saline, rather than blood,
was used. Also, mechanical, rather than bioprosthetic, valves were used
because bioprosthetic valves are destroyed by microorganisms that

proliferate in the mock loop.
Animal Studies. Because of the limitations of the mock loops in
demonstrating the interaction of the systems with a living organism and
the need to assess circulatory performance, animal studies are being
conducted. Previous criteria for testing in animals specified a period of
testing twice as long as the intended implant period except for the
temporary devices. This is impractical for chronic implants. The current
NHLBI thinking is that tests of 4-6 months provide useful results
regarding biocompatibility, bleeding, thrombosis, infection, embol ismcm—t

death.

Animal studies also have their limitations. There are substantial species
differences between the animal model and the human being. Also, the
implanted configuration of this system must be altered to fit an animal
rather than a human being. Adverse events that occur during animal
testing may or may not occur in humans because of the species difference.
It is of interest that in testing the intra-aortic pump there were more
complications in the animals than there were in humans (13). Animal
studies, then, provide some indication of potential complications and
hazards but it is felt that an implant period more than 5 months is not
useful and that human implantation represents a major challenge that

cannot be completely studied using animals.

Clinical Ventricular Assist Program. When animal testing is completed,
it is expected that 2 clinical centers will be selected to implant a total
of 20 LVAS’s in 20 patients over a two year period. This program will

focus on the many unanswered questions of device/patient interface. Each
patient will be followed for a minimum of 2 years or until death. The

first implants are expected to begin in early 1991.

The formal organization of the study (14-16) (Figure 3) will include the
two Clinical Centers, the Production Center, and a Data Coordinating
Center. The trial will be administered by a Steering Committee composed
of the investigators and by a member of the NHLBI Program Office. This
Steering Committee will develop the collaborative protocols to be usp
the study. It will be independently reviewed by a Safety, arid Data

4g a th
ad 2

Monitoring Committee that reports to the NHLBI. ( w av’) pote
During Phase I of the program, the investigatofs will focus on patient
entry criteria, protocol development and /F investigational device
approval. Patient implants will begin during Phase II after NHLBI

approval of all aspects of the protocols.

The three phases of the study will evaluate the safety and efficacy of the
LVAS over a protracted period of time. The device readiness testing
program has previously demonstrated the engineering design, and the human
investigation will study the long term response of the patient and the
ability of the device to function appropriately in a human being following

its implantation.

Patients for this study will have congestive heart failure and be severely
symptomatic. They will be candidates for cardiac transplantation who are

unlikely to receive transplant because of age or other factors.
wrell be o>
Expectations. Thik.t-dthe first time that a totally implantable LVAS has
been used. Special * cons iderat ion will be given to infectious and
thromboembolic complications (17). The results of this sort of long term
implant are not predictable, but a useful starting point is to examine
some of the results from the bridge-to-transplant experience. For
instance, in one series 72% of bridge patients were transplanted and 69%
of them were discharged alive (10). This was a heterogenous patient
population, studied at several different centers. Also, the data are
uncontrolled but it is likely that all the patients would have died if a
bridge had not been available. A particular concern is the fact that
17/40 patients developed serious infections and 9 died prior to discharge.
Of the 8 patients who developed infections after implant, 2 died of
infection, and 1 died of multiple organ system failure. The development
of an infection in 20% of the patients after implant is of particular
concern because the rate of infection is likely to increase as devices are
left in place for longer periods of time. Additionally, the ability to
eradicate a device based infection without device removal must be regarded

as problematic. In addition, 7.5% experienced neurological events that

were thought to be embolic in origin.

In summary, then, infection and thrombosis are problems of unknown but
probably substantial magnitude. Recent clinical experience provides some
encouraging, although limited, evidence of the potential viability of
this type of technology. Fifty-seven "bridge" patients (18) were

implanted with a ventricular assist system designed for long term use.
One system was electrically powered via a percutaneous lead, and the other

was air driven. Thirty-three patients were transplanted and 27 were

discharged alive.

Two of 57 patients with complex tissue matching requirements in another
study (19) were successfully bridged to transplant after 125 and 132 days
of support with an implantable ventricular assist system powered
percutaneously. These two patients were ambulatory, exercised regularly,
and previous organ dysfunction resolved after device implant. Patients
enjoyed normal organ function and a reasonably good quality of life while
confined to a hospital setting. These results are significant in that
they are the longest use of devices specifically developed for chronic
human use. Of note is the fact that these implants exceeded the 112 days

that Barney Clark lived with the first chronic artificial heart implant

(20).

The Implantable Artificial Heart. Many of the patients who require
mechanical circulatory support may require a complete replacement. In
1988 the NHLBI funded the first program targeted solely at development of
an implantable artificial heart. These systems are to be electrically
powered, tether-free and designed for 5 years of operation. These are
rigorous requirements but are necessary if systems are to evolve which

will benefit patients at a moderate price and have a truly long lifetime.

The targeted program to develop an artificial heart has followed many

years of research aimed at solving basic problems involved in perfecting

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this technology. It is only now that data suggest that the implantable
artificial heart is feasible. Competing priorities limit fiscal
resources available for artificial heart development but it is felt that

the NHLBI is now in a position to move ahead with this program.

In order to provide a continuing evaluation of need for and feasibility of

a mechanical heart the +S. Institute of Medicine™has been asked to
(rin ble try erferts of DA cy ererltot kar Lote, arn
study the artire artificial heart program, and_their—repert— is eagerly awaite

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References

Mark M. Levinson, Richard G. Smith, Randall C. Cork, et al. Vol
10(3), page 236-244, 1986

Stamler J. Epidemiology, established major risk factors, and the
primary prevention of coronary heart disease. In: Parmley WW,
Chatterjee K, eds Cardiology, Vol 2, Chl, Philadelphia: JB
Lippincott Company, 1988

CONSENSUS Trail Study Group. Effects of enalapril on mortality in
severe congestive heart failure. N Engl J Med 1987;316

Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator
therapy on mortality in chronic congestive heart failure. N Engl J
Med 1986;314:1547.

McKee PA, Castelli WP, McNamara PM, et al. The natural history of
congestive heart failure: The Framingham study, N Engl J Med
1971;285;1441-6

Artificial Heart and Assist Devices: Direction, Needs, Costs,
Societal and Ethical Issues, NIH Publication No. 85-2723;May 1985

Shikles JL, Schupp AR, Hogberg RB. Heart Transplants: Concerns
about cost, access and availability of donor organs. Government
Accounting Office Report, 1989, p. 21.

Assisted Circulation, Edited by Felix Unger, Springer-Verlag, New
York, pages 87-95;1979

Bernhard, WF, Berger, RL, McCormick, N, Stety, JD, Klein, MD,
Ryan, TH, and Carr, JG. Successful Use of a Paracorpreal Left
Ventricular Assist Device in Man. JAMA 243:46-49, 1980

Farrar, DJ, Hill, JD, Gray, LA, et al: Heterotopic Prosthetic
Ventricular as a Bridge to Cardiac Transplantation. N Engl J Med,
318:333-340, 1988

RFP NHLBI 84-1; Device Readiness Testing of Implantable
Ventricular Assist Systems

Altieri FD, Watson JT, Taylor KD. Mechanical Support for the
Failing Heart. Biomaterials Applications, Vol 1, pages 106-157,
1986

Rosenweig J, Chatterjee S$, Merino F. Treatment of acute
Myocardial Infarction by Counterpulsation: Experimental Estimate

and Clinical Experience, J Thoracin and Cardiovascular Surgery
59:243-250, 1970

RFP NHLBI HV-89-10: Clinical Center for the Evolution of
l2
15.

16.

17.

18.

19.

20.

Implantable Ventricular Assist Systems for Human Subjects with
Chronic Refracting Heart Failure, 1989

RFP NHLBI HV-84-01 (R88): Clinical Ventricular Assist System
Production, Support and Evaluation, 1988

RFP NHLBI HV-89-9: Data Coordinating Center for the Evolution of
Implantable Ventricular Assist Systems for Human Subjects with
Chronic Refracting Heart Failure, 1989

Paul Didisheim, Don B. Olsen, David Farrar, et al. Infections and
Thromboembolism with Implantable Cardiovascular Devices

Personal Communication: Summary Data provided by Dr. Peer Portner,
Baxter-Novacor, and Mr. Victor Poirier, ThermoCardiosystems, Inc.,
Oakland, CA., and Woburn, MA.

Personal Communications: Dr. Bartley Griffith, University of
Pittsburgh School of Medicine, Pittsburgh, PA and Dr. 0. Howard
Frazier, Texas Heart Institute, Houston, TX

W.C. DeVriex, the Permanent Artificial Heart: Four Care Reports.
JAMA Vol. 259, No. 6, page 844-859, 1988

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Figure l.

Figure 2.

Figure 3.

Legends

Schmetic showing the major components of an implantable left

ventricular assist system. BST = belt skin transformer, ECP

= electronics control and power, EPSM = external power source
and status monitor, VVC - variable volume compensator.

Mock circulatory loop with left ventricular assist system in
place. BST = belt skin transformer, ECP = electronics
control and power, EPSM = external power source and status
monitor, VVC - variable volume compensator.

Organizational structure for the study of the implantable
left ventricular assist system. NHLBI = National Heart, Lung
and Blood Institute.

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