Laboratory Investigation

Continuous-Flow Total Artificial Heart

Supports Long-Term Survival of a Calf
The development and clinical use of continuous-flow left ventricular assist devices (LVADs) stimulated our interest in developing a total heart replacement with continuous-flow rotary blood pumps. We constructed a continuous-flow total artificial heart (CFTAH) from 2 HeartMate II axial-flow LVADs and used this CFTAH to replace the native heart of a calf. The purpose of this experiment was to study the effects of total continuous flow on physiologic parameters at rest and during exercise after the animal recovered from surgery. We monitored pulmonary and systemic pump performance, and we assessed arterial blood gases, hemodynamic and biochemical variables, and neurohormone levels during the 7 weeks of CFTAH support. At day 36 after CFTAH implantation, the calf was exercised on a treadmill at increasing speeds for 40 minutes; total oxygen consumption, pump flow, blood pressure, and respiratory rate were monitored. Baseline hematologic levels were altered postoperatively but returned to normal by 2 weeks. We saw no signs of hemolysis or thrombosis during CFTAH support. The calf had a normal physiologic response to treadmill exercise. The animal gained weight and appeared to function normally during the study. The CFTAH operated within design specifications throughout the study. Homeostasis, end-organ and vasomotor function, and the ability to exercise are not adversely affected by 7 weeks of totally pulseless circulation in a calf. (Tex Heart Inst J 2009;36(6):568-74)

O.H. Frazier, MD William E. Cohn, MD Egemen Tuzun, MD Jo Anna Winkler, BS Igor D. Gregoric, MD

Key words: Animal; cattle; heart, artificial; hemodynamics; homeostasis; implants, experimental; left ventricular assist device; oxygen consumption; physical exertion; prosthesis design From: Cardiovascular Surgical Research Laboratories, Texas Heart Institute at St. Lukes Episcopal Hospital, Houston, Texas 77030 Funding Support: This project was supported in part by the John S. Dunn Foundation, Houston, Texas. Address for reprints: O.H. Frazier, MD, Texas Heart Institute at St. Lukes Episcopal Hospital, MC 2-114A, P.O. Box 20345, Houston, TX 77225-0345 E-mail: lschwenke@ heart.thi.tmc.edu 2009 by the Texas Heart Institute, Houston

he development of a robust, reliable, and cost-effective mechanical replacement for the failing human heart would have an important impact on the management of end-stage heart disease. Significant progress has been made in the use of externally actuated total artificial hearts (TAHs) that comprise a pair of volume-displacement, pneumatically actuated pumps; however, the development of an internally actuated device has been hampered by size constraints and limited durability.1 Therefore, the currently available TAHs have had limited clinical application. In contrast, left ventricular assist devices (LVADs) have become smaller and more durable, in large part because there has been a shift from volume-displacement pumps to continuous-flow blood pumps.2-4 This success has increased the clinical applicability of LVADs. A similar shift in approach, from volume-displacement to continuous-flow rotary blood pumps, may have a favorable impact on TAH development. However, little is known about the physiologic effects of long-term pulseless perfusion that such a TAH would produce. To study this, we constructed a continuous-flow total artificial heart (CFTAH) to anatomically replace the heart of a calf. This enabled us to evaluate the effects of continuous flow, during 7 weeks of support, on hemodynamics, neurohormonal status, end-organ function, and exercise response.

Materials and Methods

A 7-month-old, 92-kg male Corriente-crossbred calf was used for this study. We provided humane care in compliance with the Principles of Laboratory Animal Care (National Society of Medical Research) and the Guide for the Care and Use of Laboratory Animals (National Institutes of Health publication no. 85-23, revised 1996). Our Institutional Animal Care and Use Committee approved all protocols.
Continuous-Flow Total Artificial Heart

The CFTAH implanted in this calf was assembled at our institution. Central to its construction and function were 2 unmodified HeartMate II axial-flow LVADs
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(Thoratec Corporation; Pleasanton, Calif ). The inflow and outflow cannulas were removed from each of the 2 pumps and were replaced with custom-fabricated titanium adapters (Fig. 1). The adapters enabled us to anatomically replace the excised heart. The pumps were placed so that the blood flowed from the right atrium to the pulmonary pump, through the pulmonary circulation to the left atrium, into the systemic pump, and from there to the aorta. The 2 pumps were thereby in series, from a functional standpoint. Pressure ports, as well as pressure lines, were connected to enable monitoring of left atrial pressure (LAP) and right atrial pressure (RAP) after implantation. The outflow conduit comprised short segments of 14-mm Dacron graft loaded with integrated flow probes that used transittime Doppler transducers (Transonic Systems Inc.; Ithaca, NY). Each HeartMate II axial-flow pump has a separate drive line that attaches to an external battery and controller.

Surgical Technique
Our standard protocols for general anesthesia and postoperative care in calves have been described elsewhere.5 A left thoracotomy and a left-neck incision were performed. We removed the 5th rib to better expose the heart and great vessels. The power cables for both the right and left pumps were tunneled through the flank, so that they exited the skin near the lumbar spine. The

leads from 2 transit-time Doppler transducers (Transonic) and the manifold pressure lines were tunneled similarly. After systemic heparinization, routine cannulation for cardiopulmonary bypass (CPB) was performed. Normothermic CPB was initiated at 50 cc/ min/kg. The aorta was then cross-clamped, and the heart was excised by dividing the aorta and pulmonary arteries just above their respective valves and by incising the left and right atria at their circumferences, which enabled removal of the corresponding ventricles. The 2 composite inflow connectorscarefully measured and tailored to enable an acceptable configuration of the 2 pumpswere sutured to the atrial remnants with 2-0 polypropylene and felt strips. The inflow adapters were then attached to the atrial connectors. Tailored 16-mm Hemashield right- and left-pump outf low grafts connected the pumps to the ascending aorta and the pulmonary artery, compensating for the discrepancy in luminal size between the outflow grafts and the great vessels (Fig. 2). A pressure line was inserted directly into the pulmonary artery and was sutured in place for postoperative monitoring. We slowly weaned the calf from CPB while gradually increasing systemic and pulmonary pump rotational speed. Individual pump settings during CPB and throughout the postoperative period were determined from individual pump flow data obtained from the 2 transit-time flow probes and from LAP, RAP, pulmonary arterial pressure (PAP), and aortic (systemic arterial) pressure (AoP). After routine closure, the calf was transported to the intensive care unit of our animal facility and positioned in a stanchion for postoperative recovery. A drip of furosemide (10 mg/hr), isoproterenol (1 g/min), dopamine (5 g/kg/min), and nesiritide (0.01 g/kg/min) was started upon the calfs arrival in intensive care.
Follow-Up and Data Collection

Fig. 1 Left diagram: The continuous-flow total artificial heart comprises 2 HeartMate II axial-flow pumps. The inflow ends of the pumps are attached by externally supported polytetrafluoroethylene grafts to the left and right atrial cuffs (A and B, respectively), which are fabricated from a composite of Dacron polyester, silicone, and fiberglass. This construction enables the pumps to be sutured to the left and right atrial remnants (C and D, respectively) after excision of the heart. The outflow grafts of the pumps are sutured to the cut ends of the aorta (E) and pulmonary artery (F). Right diagram: The custom titanium fittings on the pump inlet (G) and pump outlet (H) are shown through a transparent section of inflow, and by removing the outflow graft.

An infusion of heparin (10 g/kg/hr) was started about 12 hours postoperatively. Measurements of pulmonary and systemic pump performance, including pump speed in revolutions per minute (rpm), pump power consumption in watts, flow probe data in liters per minute (L/ min) and pressure data from the RAP, LAP, PAP, and AoP lines, were recorded continuously throughout the postoperative period by a multichannel data-acquisition system (Ponemah System, version 3.3; Data Sciences International; St. Paul, Minn). We examined arterial blood gases hourly during the 1st day, and as needed thereafter. Hematologic and biochemical values were analyzed daily for signs of kidney or liver dysfunction, anemia, hemolysis, or infection. Furthermore, we examined neurohormone levels, including renin, angiotensin-converting enzyme (ACE), epinephrine, norepinephrine, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and endothelin-1 (ET-1), as often as once a day until the studys termination. NorContinuous-Flow TAH Supports Long-Term Survival

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On postoperative day 36, the calf was placed on a motorized treadmill (Safe-T-Mill Treadmill, Good Horsekeeping, Inc.; Ash Grove, Mo); total body oxygen consumption (VO2 = CO [O2a O2v]) and blood lactate levels were calculated at rest and at several treadmill speeds and levels of exertion. Pump flows were recorded at constant speeds. At the studys termination on day 48, we performed a necropsy, which included gross and histologic study of all vital organs and careful examination of the CFTAH.

Results
Postoperative Course

Fig. 2 A) Orientation of left outflow (LO) and right outflow (RO) grafts and left inflow (LI) cuff after implantation of a continuousflow total artificial heart in a calf. B) Contrast injection while the pump is running shows the left and right pumps (LP and RP, respectively) and the left inflow cuff (LIC). Ao = aorta

mal neurohormone values were calculated as the mean SD of the values obtained in 20 healthy cows. Urine output was monitored hourly throughout the study. During the immediate postoperative period, we adjusted the increased peripheral vascular resistance and the expected hypertensive response of the circulation to continuous flow as needed by titrating vasoactive agents, including sodium nitroprusside, BNP, isoproterenol, and nitroglycerin. Pulmonary and systemic pump flow was balanced by adjusting systemic and pulmonary pump rpm to achieve adequate flow (usually from 10 to 14 L/min) and to maintain LAP, RAP, PAP, and AoP in the physiologic range. Diuresis was achieved with a furosemide drip and with supplemental bumetanide hydochlorthiazide. The calf was weighed throughout the study to monitor growth.
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The calf regained consciousness within 2 hours of arrival in the intensive care unit. By postoperative day 1, the calf was standing for several hours at a time and had resumed oral intake. Isoproterenol was stopped during the 1st postoperative day but was resumed on day 11 to treat persistent hypertension. By postoperative day 3, the calf was tolerating a full diet and had been weaned from the ventilator. Low-dose dopamine for renal perfusion was stopped on postoperative day 4. Arterial blood gases showed that oxygenation and ventilation were adequate while the calf was breathing spontaneously on a tracheostomy cannula. Blood gas results remained normal throughout the postoperative course until hours before study termination. The tracheostomy cannula was removed on day 28. Tracheal stenosis subsequently developed, resulting in respiratory distress that necessitated euthanasia on postoperative day 48. The cause of the respiratory distress was not apparent premortem and was discovered only upon postmortem evaluation of the trachea. Hematocrit, hemoglobin, and platelet levels dropped below baseline levels on postoperative day 1 and gradually returned to baseline levels over the next 2 weeks. Plasma-free hemoglobin, a sensitive indicator of hemolysis, was within normal range throughout the study. On the basis of values obtained in 20 normal cows, the following neurohormone levels were considered normal: adrenaline (1.5 pg/mL); noradrenaline (11 12.2 pg/mL); renin (1.8 1.1 pg/mL); ACE (78.7 71.3 U/ mL; ET-1 (223 559 pg/mL); ANP (26.8 pg/mL); and BNP (25.8 34.7 pg/mL). Changes in neurohormone levels throughout the study are shown in Figures 3 through 5. We observed a 2- to 3-fold increase in adrenaline and noradrenaline levels immediately after surgery, which returned to near-baseline levels in 7 to 10 days (Fig. 3). Plasma renin levels and all measures of renal, hepatic, and pulmonary function were normal throughout the study, except for 2 spikes seen on day 15 and day 30; these increases may be the result of a sampling error. The ACE levels decreased immediately after surgery but remained within normal range. The ET-1 levels increased slightly after surgery but also remained within normal
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range throughout the study (Fig. 4). In addition, levels of the natriuretic peptides gradually increased 2- to 3-fold during the study (Fig. 5). The levels of natriuretic pep-

tides, however, may have reflected the use of intravenous BNP during the postoperative period. By all indicators, the calf appeared normal throughout the postoperative period. During the course of the study, the calf gained 6 kg. He recognized his keepers, ate, drank, slept, stood at regular intervals, and had normal gastrointestinal and renal function. He also had an affinity for molasses.
Pump Hemodynamics

Fig. 3 Adrenaline and noradrenaline levels in a calf that was supported for 7 weeks with a continuous-flow total artificial heart.

Fig. 4 Angiotensin-converting enzyme (ACE), endothelin-1 (ET1), and renin levels in a calf that was supported for 7 weeks with a continuous-flow total artificial heart.

The right and left pumps operated without devicerelated problems throughout the study. Left-to-right hemodynamic balance was achieved by maintaining RAP between 5 and 15 mmHg. To do this, the right-pump speed was varied between 5,590 and 13,200 rpm; the left-pump speed was varied between 9,600 and 14,990 rpm. Left-pump flow remained consistently higher (1.4 1.1 L/min) than right-pump flow, because the direct return of bronchial blood flow to the left atrium normally results in a slight increase in left ventricular flow over right ventricular flow. A simple algorithm was used to adjust pump rotational speeds. The left-pump flows were generally maintained at an rpm rate that kept systemic pressure between 80 and 95 mmHg. Alterations of flow in the postoperative period were achieved by changing the rpm of the rightsided pump. Pharmacologic manipulations were used for blood pressure control and for diuresis. By day 14, vasopressor dosage was minimized, and flow and pressure were autoregulated. During speed adjustments, the presence of pump-topump interdependence was evident. An increase in the rotational speed of 1 pump resulted in an almost instantaneous increase in the filling pressure of the other. Because the output of axial-flow pumps (and all rotational pumps) is very sensitive to the pressure gradient across the pump, this increased filling pressure resulted in an increase in pump flow, despite the fact that the pump rotational speed remained constant. Therefore, an increase in the rotational speed of 1 pump results in an increase in flow of both pumps.
Treadmill Study

Fig. 5 Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels in a calf that was supported for 7 weeks with a continuous-flow total artificial heart.

On postoperative day 36, the calf exercised on a treadmill for about 40 min at increasing speeds, followed by a 10-min period of decreasing speed (Fig. 6). At this time, the calf was not receiving any vasoactive agents. The calf showed no signs of exhaustion during the exercise. Breathing was normal throughout the study. The left- and right-pump flows increased as a response to increased inflow, without any adjustments to pump speeds. The calf was returned to his stanchion and appeared to be in normal condition. The analysis of arterial blood gas samples taken during the treadmill test showed a normal total body oxygen consumption (VO2) curve (Fig. 7). Blood levels of lactate did not
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Fig. 6 The calf exercised on a treadmill for about 40 minutes on postoperative day 36.

Fig. 7 Total body oxygen consumption (VO2) and pump flows at baseline, at various treadmill speeds, and at rest in a calf 36 days after implantation of a continuous-flow total artificial heart. Leftand right-pump rotational speeds were kept constant at 13,000 rpm and 11,000 rpm, respectively.

change with increasing treadmill speeds or at rest, remaining between 1 and 1.2 mmol/L.
Necropsy

On day 47, the calf became increasingly dyspneic. We suspected a pump failure, so on day 48 the animal was humanely euthanized. A nonobstructive kink in the left-pump outflow graft was found upon necropsy. The inner surfaces of both pumps and their outflow grafts showed no thrombus. The trachea had severely stenosed to 5 mm in diameter at the insertion site of the tracheostomy cannula. This was the presumed cause of distress. The lungs showed no signs of pulmonary edema or atelectasis. The liver appeared unremarkable in the gross evaluation and had defined edges. Both kidneys showed small infarcts. No significant findings were observed on gross evaluation of the brain.

Discussion
In this study, we have shown that a calf can maintain homeostasis with pulseless circulation and that endorgan function, vasomotor function, neurohormonal status, and the ability to exercise are not adversely affect572
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ed by the presence of pulseless circulation. The present study is part of a series of studies we have undertaken to improve our understanding of the physiologic consequences of long-term, pulseless circulation. Our findings here extend those of our previous study in which we reported the 3-week survival of a calf after its heart had been removed and replaced with 2 Jarvik 2000 rotary pumps.5 Total artificial hearts have been used successfully as rescue devices for patients facing imminent death. In addition, TAHs have been used with some success as destination devices to sustain a small number of gravely ill patients who were not candidates for transplantation.6 The most frequently used TAH has been powered by a large, extracorporeal, pneumatically actuated driver, which makes this type of TAH poorly suited for long-term use. Several innovative, self-contained mechanisms have been developed to overcome this deficiency and to eliminate the need for an external driver; nevertheless, the size, complexity, and expense of the resultant TAH systems have hindered their widespread application.7 A self-contained TAH that exploits the ongoing advances in continuous-flow rotary blood pump technology offers an attractive alternative to the pulsatile volume-displacement approach.8 Continuous-flow blood pumps have several favorable properties. Small, durable, and reliable, rotary blood pumps require no external driver and are energy efficient. A CFTAH that comprises 2 rotary blood pumps, 1 each for the systemic and pulmonary circulation, is easier to implant and less susceptible to mechanical wear than are current pulsatile TAH designs. Moreover, because of its intrinsic flow-pressure sensitivity, the rotary blood pump enables balance between the systemic and pulmonary circulations, a physiologic necessity that has been a challenge to satisfy with the totally implanted pulsatile TAH. Current clinical experience with the use of rotary blood pumps as LVADs is extensive. As of the end of 2008, various types of rotary LVADs had been implanted in more than 3,000 patients and had operated continuously in patients for more than 7 years.9 These clinical results further support the integration of rotary blood pumps into the next generation of TAHs. In most patients with rotary LVADs, some degree of arterial pressure fluctuation is maintained because of the varying inflow pressures that result from ventricular contraction. This increased inflow pressure increases flow from the continuous-flow LVAD. Patients with absent or attenuated pulses have generally shown no evidence of end-organ dysfunction or hypoperfusion attributable to reduced pulse pressure. However, little is known about the long-term physiologic effects of completely pulseless perfusion. In calves implanted with TAHs that mimic properties of the native heart, exercise capacity has been meaVolume 36, Number 6, 2009

sured in terms of total body oxygen consumption (VO2) and lactate values at increasing treadmill speeds.10-12 In our study, we showed that VO2 increased in response to exercise in a calf implanted with a CFTAH. In contrast with results described in studies of pulsatile TAHs,10 we report here that blood lactate levels in our calf remained similar to pre-exercise levels, despite increased body oxygen consumptionan indication of good perfusion. Arterial blood gases remained normal. Reports of neurohormonal assessments in animals supported with CFTAHs are few.13 In our study, the hyperadrenergic response that we documented in the postoperative period was consistent with the high afterload (high AoP). Continuous-flow pumps are preloadand afterload-sensitive, so RAP, LAP, and systemic and pulmonary vascular resistances are major determinants of pump output. Our results are consistent with those of Golding and colleagues13; however, our increases in adrenaline and noradrenaline levels were less than the increases they reported. In addition to adrenergic system activation, we saw a gradual increase in ET-1 levels after surgery; yet levels were still within the normal range throughout the study. This finding may be related to the direct endothelial effect of continuous-flow conditions. Atrial natriuretic peptide and BNP are natriuretic peptides produced mainly in the atria and ventricles, as well as in the brain, adrenal glands, thyroid, and spleen in patients with end-stage heart failure. These peptides have been reported to induce balanced vasodilation and increase renal blood flow, glomerular filtration rate, and urine output in patients with the AbioCor TAH.14 Although our healthy calf was implanted with a dual CFTAH, we used infusions of recombinant human BNP (nesiritide) to assist in decreasing systemic and pulmonary blood pressures as well as in augmenting diuresis. Circulating natriuretic peptides gradually increased during the study. The ACE and renin levels were within physiologic levels. Of particular interest is our observation that the renin levels were within physiologic limits. In 1960, Saxton and Andrews 8 theorized that the ideal heart replacement would be a continuous-flow pump. They noted that the automaticity of such pumps to increasing inflow pressure parallels the automaticity of the Starling response of the normal mammalian heart. The senior author (OHF) has always believed that a small, durable heart-replacement device could become a reality if rotary-pump technology could be developed that would effectively duplicate the response of the normal heart to the varying physiologic needs of the mammalian circulation. Our present and previous studies have shown that this feedback mechanism can be duplicated by a rotary blood pump even at a constant rpm rate. Furthermore, the treadmill study showed that the increase in pump outflow was analogous to the normal physiologic response of the heart to exercise. This
Texas Heart Institute Journal

automatic response to the increased venous return of exercise demonstrates the reality of the Starling-like response of continuous-flow heart-replacement pumps. The same automatic response occurs with decreased return. The responses to changes in cardiac output are immediate. These experiments support the feasibility of this approach to total cardiac replacement. In 1957, Akutsu and Kolff 15 replaced the heart of a dog with a pulsatile TAH, and the animal survived for several hours. This experiment showed that replacing the heart with a pulsatile pump was feasible. However, it took more than 40 years for an implantable, pulsatile TAH to be used clinically. In 2006, we began experiments using 2 nonpulsatile, continuous-flow pumps for total heart replacement.
Conclusion

We report a study of a calf maintained on pulseless circulation for 48 days with a continuous-flow total artificial heart that we constructed from 2 HeartMate axial-flow pumps. Data obtained over the 7-week period show that pulseless circulation did not adversely affect homeostasis or the ability to exercise. Furthermore, the calf maintained normal physiologic function and growth throughout the study. The continuous-flow pump is more durable, more physiologically responsive, and more anatomically compatible for use in all sizes of patients than is the pulsatile pump. Therefore, we believe that a continuous-flow total artificial heart will be more effective for long-term use, and we have shown that the initial approach is feasible. We hope that the continuous-flow total artificial heart will become a clinical reality in a timelier manner than did the pulsatile total artificial heart.

References
1. Frazier OH. Prologue: ventricular assist devices and total artificial hearts. A historical perspective. Cardiol Clin 2003;21(1): 1-13. 2. Potapov EV, Koster A, Loebe M, Hennig E, Fischer T, Sodian R, Hetzer R. The MicroMed DeBakey VAD--part I: The pump and the blood flow. J Extra Corpor Technol 2003;35 (4):274-83. 3. Frazier OH, Shah NA, Myers TJ, Robertson KD, Gregoric ID, Delgado R. Use of the Flowmaker (Jarvik 2000) left ventricular assist device for destination therapy and bridging to transplantation. Cardiology 2004;101(1-3):111-6. 4. Nojiri C, Kijima T, Maekawa J, Horiuchi K, Kido T, Sugiyama T, et al. Development status of Terumo implantable left ventricular assist system. Artif Organs 2001;25(5):411-3. 5. Frazier OH, Tuzun E, Cohn WE, Conger JL, Kadipasaoglu KA. Total heart replacement using dual intracorporeal continuous-flow pumps in a chronic bovine model: a feasibility study. ASAIO J 2006;52(2):145-9. 6. DeVries WC. The permanent artificial heart. Four case reports. JAMA 1988;259(6):849-59. 7. Frazier OH, Dowling RD, Gray LA Jr, Shah NA, Pool T, Gregoric I. The total artificial heart: where we stand. Cardiology 2004;101(1-3):117-21.

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8. Saxton GA Jr, Andrews CB. An ideal heart pump with hydrodynamic characteristics analogous to the mammalian heart. Trans Am Soc Artif Intern Organs 1960;6:288-91. 9. Westaby S, Siegenthaler M, Beyersdorf F, Massetti M, Pepper J, Khayat A, et al. Destination therapy with a rotary blood pump and novel power delivery. Eur J Cardiothoracic Surg 2009 Jul 8. [Epub ahead of print] 10. Kamohara K, Weber S, Klatte RS, Luangphakdy V, Flick CR, Ootaki Y, et al. Hemodynamic and metabolic changes during exercise in calves with total artificial hearts of different sizes yet similar output. Artif Organs 2007;31(9):667-76. 11. Yozu R, Golding LA, Shimomitsu T, Jacobs G, Watanabe T, Harasaki H, Nose Y. Exercise response in chronic nonpulsatile and pulsatile TAH animals. Trans Am Soc Artif Intern Organs 1985;31:22-7.

12. Chiang BY, Pantalos G, Burns GL, Long JW, Khanwilkar PS, Everett SD, et al. Anaerobic threshold in total artificial heart animals. ASAIO J 1994;40(3):M335-8. 13. Golding LR, Jacobs G, Murakami T, Takatani S, Valdes F, Harasaki H, Nose Y. Chronic nonpulsatile blood flow in an alive, awake animal 34-day survival. Trans Am Soc Artif Intern Organs 1980;26:251-5. 14. Delgado R 3rd, Wadia Y, Kar B, Ethridge W, Zewail A, Pool T, et al. Role of B-type natriuretic peptide and effect of nesiritide after total cardiac replacement with the AbioCor total artificial heart. J Heart Lung Transplant 2005;24(8):1166-70. 15. Akutsu T, Kolff WJ. Permanent substitutes for valves and hearts. Trans Am Soc Artif Intern Organs 1958;4:230-5.

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