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30 End-Stage Cardiomyopathy

Ventricular Assist Devices

SOON J. PARK, MD

CONTENTS

INTRODUCTION MECHANICS

CLINICAL EXPERIENCE FUTURE

SUMMARY REFERENCES

1. INTRODUCTION

Heart disease is the number one cause of morbidity and mortality in Western society. This problem has become well recog- nized in the literature over the past few decades, and researchers have mounted intense efforts to remedy the situation. A heart transplant is clearly the most effective therapy for patients with advanced heart failure; it is able to restore them to a near-normal lifestyle, and long-term survival is excellent (1). However, the number of donor hearts available for transplantation is limited to only about 2000 each year, compared to over 10,000 people each year who could benefit from such a therapy.

Successful development of a total artificial heart or advanced ventricular assist devices could help resolve this imbalance.

Development efforts to do so were organized under the National Institutes of Health leadership in 1964. The ideal pump was originally thought to be a totally implantable device, with an electrical motor that could completely replace the heart function physiologically as well as anatomically. Yet, despite many decades of research, we still do not have such a device. In the mid-1970s, parallel research on ventricular assist devices took place; the result was a variety of ventricular assist devices described in this chapter.

2. MECHANICS

2.1. Volume Displacement Pumps

The human heart is a volume displacement pump. To create a unidirectional flow with a single pumping chamber, inflow and From: Handbook of Cardiac Anatomy, Physiology, and Devices Edited by: P. A. Iaizzo © Humana Press Inc., Totowa, NJ

outflow valves are required. For example, in the left ventricle of the native heart, the mitral valve functions as the inflow valve;

the aortic valve functions as the outflow valve. The result is unidirectional blood flow. Similarly, ventricular assist devices designed as volume displacement pumps would require these two types of valves. Some ventricular assist devices have incorporated mechanical prosthetic valves; others have utilized bioprosthetic valves (Fig. 1). Importantly, the choice of valve mandates different types of anticoagulation therapy and thus leads to a different natural history of valve failure.

A major obstacle in designing clinically acceptable ventricular assist devices has been the array of problems associated with the blood contact surfaces. Specifically, any type of stagnant blood flow within the pocket of the pumping chamber can result in thrombus formation. Also, the artificial blood contact surface is quick to promote a clotting cascade, resulting in significant thromboembolism. Yet, initial attempts at making the blood contact surface as smooth as possible have not yielded satisfactory outcomes. One proposed solution for this was the construction of textured blood contact surface to promote early platelet and fibrin deposition, which resulted in formation of stable pseudointima; such a design was applied in the HeartMate ® system (Thoratec Corporation; Pleasanton, CA) (Fig. 2) (2).

The mechanism involved in ejecting blood varies from model to model. Some ventricular assist devices either have a compressible blood-filled sac or a flexible diaphragm within a hard shell. In others, compressed air serves as a medium to collapse either the sac or the diaphragm and thereby eject

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Exter Batt(

/ Pa¢ ^tMate^{/E LVAD}

System Air Vent with Controller Vent Filter

inserted

Fig. 1. Schematic of a HeartMate ® SNAP-VE ventricular assist device system. One can see the internal connections at the apex of the left ventricle where there is inflow into the device and outflow connected directly to the aorta. This system utilizes an external battery pack and controller system. LVAD, left ventricular assist device.

Fig. 2. (A) External view of an actual HeartMate®-VE. This pump generates a systolic pressure of 200 mmHg, utilizing a slow torque motor with high dp/dt. (B) Shown are the textured blood contact surfaces that promote early platelet and fibrin deposition, resulting in formation of a stable pseudointima. LVEDP, left ventricular end-diastolic pressure. Reprinted with permission from Thoratec Corporation.

blood. Compressed air seems to provide a simple and reliable way of either activating the diaphragm or compressing the sac, with a pressure more comparable to a physiologically acceptable waveform. However, this design requires a bulky driving console, compromising the patient's mobility.

In other ventricular assist devices, the diaphragm is acti- vated by a slow-torque electrical motor that is small enough to be incorporated into the implantable unit. Thus, patient mobility is significantly improved with this type of ventricular assist device compared to the ones driven by a pneumatic console.

Because the diaphragm is propulsed by a noncompressible metal, the pressure waveform during ejection is less physiological, with a rather rapid rise in pressure over time (dp/dt); the peak dp/dt could be many times higher than that generated by a normal heart. This could translate into a significant mechanical load on the inflow valve during the ejection phase and subsequent premature inflow valve failure. Furthermore, such an abnormal pulse wave and sudden increase in patient's cardiac output could adversely affect the central nervous system by causing cerebral edema.

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A volume displacement pump goes through a natural fluc- tuation in pressure in the driving chamber, but it either must have an implantable compliance chamber or it must be vented to the outside. Yet, to date ventricular assist devices with a totally implantable compliance chamber are bulkier to implant, and the compliance chamber itself has to be accessed from time to time to compensate for gradual dissipation of gas in the chamber. These features may thus compromise its application in the clinical setting, although its total implantability is attractive.

On the other hand, the pumps with external vents still cannot be totally implantable. The driveline exit site can be a significant source of discomfort and infection. Even though patient mobility is significantly improved with an electrical motor-driven system, these systems tend to be bulky and heavy, resulting in pain and abdominal discomfort. Furthermore, this type of system requires replacing the entire system, rather than just switch- ing out the external driving console (as in the air-driven system), when the motor fails.

Some of the volume displacement pumps are designed to be placed outside the body, with inflow and outflow cannulas attaching the system to the ventricle and aorta. This type of system has the benefit of versatility, and even small patients can be supported with these paracorporeal pumps. However, an externally located pump attached to a driving console com- promises the patient's quality of life significantly.

Even though volume displacement pumps, with their relatively simple mechanical construction, are effective in replacing cardiac function in the clinical setting, to date they continue to have many shortcomings. Accordingly, different technologi- cal platforms are under evaluation for the next generation of ventricular assist devices.

2.2. Axial Flow Pumps

Archimedean pumps have been in use for centuries as a very effective means to transport fluids. A similar type of axial flow pump that featured rapid rotation of an impeller in a blood system was thought to be impractical given concerns about red blood cell destruction (Fig. 3), but that theoretical concern was recently discarded when a Hemopump ® was successfully used in a clinical setting without significant hemolysis (3). The Hemopump has thus set the stage for evaluation of other types of axial flow pumps that could be used for blood. Nevertheless, with high-speed axial flow pumps, the heat generated by the motor must be sufficiently less than what the human body is able to dissipate in a physiologically acceptable manner. The amount of heat generated seems to be in an acceptable range, so it has not been a concern in creating clinically acceptable axial flow pumps.

Importantly, an axial flow pump does not require valves to create a unidirectional flow. It does not require an external vent or a compliance chamber, thus making it more likely to utilize this approach to create a totally implantable system (Fig. 4).

Furthermore, a motor attached to a turbine to drive the blood could be located even within the heart, and the outflow conduit could be connected to the ascending or descending aorta. Or, a pump could be connected to the apex of the left ventricle with an inflow cannula, and an outflow graft could be connected to the ascending or descending thoracic aorta.

Fig. 3. Relative size of the impeller blade utilized to create flow in the axial pump (compared to a pencil).

Fig. 4. Size of the Jarvik 2000 (Jarvik Heart, Inc. and Texas Heart Institute) axial flow pump, which like other ventricular assist device systems, has an inlet within the left ventricular apex and outflow connected to the aorta. The advantage of this type of system is that it will likely be totally implantable.

Depending on the motor capacity and rotational speed, an axial flow pump could function either as a partial-flow or a full-flow support device. This type of ventricular assist device functions like an open tube in terms of pressure transmission;

any pressure generated by the native heart would be transmit- ted to the distal vascular bed. Therefore, the forward flow generated by an axial flow pump could be augmented by pulsatility from the native heart. The amplitude of pressure waves would depend on the contractual state and preload of the left ventricle.

To date, there is little accumulated clinical experience with axial flow pumps compared with that of volume displacement pumps. However, initial results appeared to be encouraging, with effective circulatory support and durability (4-6). Dimin- ished pulse pressure when utilizing an axial flow pump seemed to be tolerated well in patients, at least for the short term; the

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long-term consequences of axial flow pumps have yet to be evaluated. Some axial flow pumps require a suspension of the rotor with a contact point. The concern about potential wear over time needs to be evaluated through in vivo testing, but current in vitro data seem to indicate that the actual wear may be negligible for at least a few years. Hemolysis associated with axial flow pumps has been detectable, but is considered clinically insignificant. These pumps seem to activate platelets because of the physical strain on blood cells; yet, such activation may be an important source of intravascular thrombosis and embolic complications. Currently, intense anticoagulation regimens targeting platelet activation and clotting cascade have been employed to deal with the problems of thromboembolism.

2.3. Centrifugal Pumps

The development of a rare earth-based magnet within the past few decades has provided an additional potential techno- logical platform for designing ventricular assist devices. With this technology, a flow source could be suspended and rotated in a magnetic field, avoiding any need for a contact point and thus eliminating the concern of wear of the rotor over a long period of time. Furthermore, such ventricular assist devices would likely have very little mechanical friction resistance to overcome. Pulsatile flow could also be generated by a rapid variation of rotation speeds. The blood propeller could be designed in either a turbine or centrifugal form, potentially pro- viding a reliable forward flow with pulsatility.

This type of futuristic ventricular assist device could be an open tube system as well, capable of transmitting the native heart's pressure wave. However, if the motor were to fail, the open system could result in significant regurgitant flow, wors- ening heart failure symptoms. In addition, no reliable backup support mechanism would be readily available unless specifically added (like a hand pump with volume displacement pumps).

3. CLINICAL EXPERIENCE

Before any ventricular assist device is implanted in the clinical setting, it has undergone significant in vitro and in vivo testing, including preclinical animal implant experiments. Nev- ertheless, even though the efficacy, reliability, and performance of these devices would be well understood, unexpected adverse events could be observed in the clinical setting.

As the various types of ventricular assist devices are intro- duced in a clinical setting, the initial target population should be individuals who could actually benefit from such a therapy with a minimal risk of adverse events from the device itself. Thus, the most logical place to start is with patients who are at imminent risk of death while waiting for a heart transplant. The risk/

benefit ratio seems to favor implantation of such experimental ventricular assist devices as a salvage procedure; that is, the duration of ventricular assist device support would be finite and short term, until a donor heart became available. A prospective trial utilizing such a setting was conducted by Frazier et al. (7),

and therapeutic benefit of the ventricular assist device as a bridge to a heart transplant was documented. This trial resulted in approved application of such a device as a bridge therapy to heart transplant.

The number of patients on heart transplant lists can be considered relatively few, compared with the many patients with conditions similar to end-stage heart failure. Nevertheless, because of the limited number of donor hearts available in the United States, many patients are denied a chance at heart replacement therapy. Therefore, the next logical clinical con- sideration for patients with advanced heart failure is, "Can a ventricular assist device be used to improve longevity and quality of life and not merely as a bridge to a transplant (that is, as a means to an end)?" This question was originally asked in the 1960s when the National Institutes of Health sponsored a research project on the totally artificial heart. Clearly, this question remains at center stage for any development of a circulatory support system.

More specifically, with accumulated experience from the HeartMate-VE system as a bridge to a heart transplant, answers to that question were sought through the Randomized Evalua- tion of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial under the leadership of Dr.

Eric Rose (8). That prospective randomized clinical trial compared the survival outcomes in patients with advanced heart failure who received optimal medical management vs undergoing ventricular assist device implantation.

The trial enrolled 129 patients and demonstrated statisti- cally significant benefits at 1 and 2 yr. Importantly, the ventricular assist device group had about twice the survival rate of the optimal medical management group (9). Nearly all mortality in the optimal medical management group was caused by advanced heart failure. However, infection and device failure accounted for about 60% of the mortality in the ventricular assist device group. Yet, it is considered that both of these complications could be reduced significantly over time.

The REMATCH trial clearly documented efficacy of the ventricular assist device in an evidence-based manner and set the stage for expanded indication of device implantation in the clinical setting. The FDA has now approved the Heartmate-VE as a destination therapy device to treat end-stage heart failure patients

"as a means to an end." Such approval should encourage new device development, which in turn should advance the field significantly over time and improve the quality of life and survival rate of patients with advanced heart failure symptoms (Fig. 5).

It should be noted that one of the axial flow pump devices, the DeBakey ventricular assist device by Micromed Technol- ogy, Inc. (Houston TX), is currently undergoing a clinical trial to test its efficacy as a bridge to a heart transplant device (10).

It is anticipated that many more new and different models of device systems will be evaluated in the near future in similar clinical settings.

4. FUTURE

The future of ventricular assist devices is promising. Cur- rently, we seem to be dealing with early prototypes. Many minor and major advances will take place in the field when we finally have a long-term device that can replace circulatory function. Nevertheless, any device should possess most of the following characteristics:

1. It must be totally implantable to lower the risk of infection significantly and to improve the quality of life for patients.

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Fig. 5. One of the author' s former patients standing on his tractor, taking a break from plowing his farm fields; he did this while being supported with a ventricular assist device system.

2. It must be effective enough to provide adequate blood flow to meet the variable hemodynamic needs associated with a normal lifestyle (allow for activity and mobility).

3. It must be reliable and durable. The current ventricular assist devices require a major operation to implant, and device failures require additional major surgery to change out the pumps. For FDA approval of the ventricular assist device as a destination therapy, 5-7 yr has been suggested as an acceptable length of time for durability.

4. It must be compatible with human physiology. For example, pressure wave generation over time must be acceptable to the human body, especially to the neurological system. With the axial flow pump design, diminished pulse pressure must be determined to be physiologically acceptable to the human body over the long term. Likewise, with the levitating axial flow pump design and its ability to generate adequate pulse pressures, pressure generation must be acceptable and thus likely to mimic the human physiological pressure waveform.

5. It must be small in size to ensure acceptable quality of life.

Currently, the electrical motor-driven ventricular assist device is considered bulky and noisy, with significant motion associated with the slow torque motor. The future ventricular assist device must be even smaller, thus not impinging on other organ space; moreover, it must not cause pain because of motion or heaviness.

6. It must have minimal associated thromboembolic risks.

The blood contact surface or physical property of the pro- pulsion mechanism must not trigger intravascular thrombosis. Some of the current ventricular assist devices have associated adverse blood contact properties that are being addressed by aggressive anticoagulation regimens. In the future, the need for anticoagulation must be minimal. An

optimal design would minimize the blood contact-related activation of the clotting cascade and thus cause minimal physical deformity of blood cells.

5. SUMMARY

Ventricular assist device development has been an interest- ing and gratifying clinical area of advancement for the past several decades. Importantly, many patients have been saved from imminent death by appropriate application of ventricular assist devices and subsequent heart transplant. Most of these patients have been able to add years to their lives and enjoy good health. Of clinical interest, some degree of reverse remodeling process has been confirmed in many patients during the unload- ing period of the left ventricle on the ventricular assist device.

Furthermore, a few patients have even demonstrated clinically significant myocardial recovery to the degree at which ventricular assist devices could be explanted safely.

Thus, the exact conditions under which myocardial recovery occurs and ways to enhance incidence of recovery are now under intense investigation. For example, Dr. Jacob Yacoub et al.

(Imperial College School of Medicine, Heart Science Centre, Middlesex, UK) have used Clenbutrol, a 13-2 agonist, to promote left ventricular hypertrophy and subsequent ventricular assist device removal. This particular drug is under evaluation at other centers as well to validate the initial observation made in England. Such drugs may play an important role in promot- ing reverse remodeling in failing hearts. The role of the ventricular assist devices as a bridge therapy to myocardial recovery will remain as a very intriguing concept to explore. A combina- tion of new drugs or stem cell infusion and short-term ventricular assist device support may prove to be helpful in successfully repairing failing hearts (11).

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REFERENCES

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2. Rose, E.A., Levin, H.R., Oz, M.C., et al. (1994) Artificial circulatory support with textured interior surfaces. A counterintuitive approach to minimizing thromboembolism. Circulation. 90, II87-I191.

3. Wampler, R.K., Baker, B.A., Wright, W. M. (1994) Circulatory support of cardiac interventional procedures with the Hemopump car- diac assist system. Cardiology. 84, 194-201.

4. Westaby, S., Banning, A.P., Jarvik, R., et al. (2000) First permanent implant of the Jarvik 2000 Heart. Lancet. 356, 900-903.

5. Noon, G.P., Morley, D., Irwin, S., Benkowski, R. (2000) Develop- ment and clinical application of the MicroMed DeBakey VAD. Curr Opin Cardiol. 15, 166-171.

6. Wieselthaler, G.M., Schima, H., Hiesmayr, M., et al. (2000) First clinical experience with the DeBakey VAD continuous-axial-flow pump for bridge to transplantation. Circulation. 101,356-359.

7. Frazier, O.H., Rose, E.A., Oz, M. C., et al. (2001) Multicenter clinical evaluation of the HeartMate vented electric left ventricular assist system in patients awaiting heart transplantation. J Thorac Cardiovasc Surg. 122, 1186-1195.

8. Rose, E.A., Moskowitz, A.J., Packer, M., et al. (1999) The REMATCH trial: rationale, design, and end points. Randomized Evaluation of Mechanical Assistance for the Treatment of Conges- tive Heart Failure. Ann Thorac Surg. 67,723-730.

9. Rose, E.A., Gelijns, A.C., Moskowitz, A. J., et al. (2001) Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med. 345, 1435-1443.

10. Goldstein, D.J. (2003) Worldwide experience with the MicroMed DeBakey Ventricular Assist Device as a bridge to transplantation.

Circulation. 108, 11272-11277.

11. Suzuki, K., Murtuza, B., Smolenski, R. T., et al. (2001) Cell transplantation for the treatment of acute myocardial infarction using vascular endothelial growth factor-expressing skeletal myoblasts.

Circulation. 104, 1207-1212.