Valve replacement: Present status of homograft valves

Valve R e p l a c e m e n t : Present S t a t u s of H o m o g r a f t Valves W. W. Angell, P. deLanerolle, and N. E. S h u m w a y

R E A T M E N T of valvular disease has been one of the most popular procedures in cardiac surgery. Although first efforts were directed toward valve repair, it soon became evident that total replacement was essential in a majority of cases and that the success of human cardiac valve replacement is dependent in part on the type of valve used for replacement. Valve substitutes evolved as either biologic tissue grafts or mechanical prostheses. Both the aortic homograft and the caged-ball prosthesis have had a similar longevity of experience. Although the total number of tissue grafts is minor in comparison with the prosthetics, interest in homografts persists. This paper summarizes the present status of homograft valve usage, including discussions of sterilization, storage, viability, the morphologic and histologic appearance of long-term implants, and the morbidity and mortality following clinical usage. For comparison, it will also present a brief summary of the status of the prosthetic and biologic valves presently used clinically and a critical evaluation of the relative efficacy of the various valve types.

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Interest in homograft valves was kindled by Lain and his associates ~ when they implanted fresh aortic valve homografts in the descending aorta of dogs in 1952. Murray ~ applied a somewhat modified method clinically, and some of these patients were shown by angiography to have mobile leaflets 7-13 yr after implantation? Ten yr after Lam's work, Duran and Gunning 4 outlined a method for dissecting and implanting aortic valve homografts in the subcoronary position. This experimental work was applied by Ross, 5 and the first clinically successful orthotopic implantation of a homograft valve was accomplished in 1962. In the same year, Barratt-Boyes employed fresh valve transplantation in a group of 16 patients, 6 and a recent report 7 on this group shows good persistent function in 70% of these cases. Subsequently, homograft valve transplantation was undertaken enthusiastically by others, s-tz and follow-up studies ~3-~7 and long-term results ~s-2~ have established the feasibility and value of using homograft valves for the replacement of diseased and nonfunctioning heart valves in all intracardiac positions. From the Division of Cardiovascular Surgery, Veterans Administration Hospital, Palo Alto, Cal~f, the Santa Clara Valley Medical Center, San Jose, Calif., and the Department of Surgery, Stanfl)rd University School of Medicine, Stanford, Calif. W. W. Angell, M.D.: Chief Cardiovascular Surgery, Veterans Administration Hospital, Palo Alto, Calif., and Western Heart Associates. San Jose, Calif. P. deLanerolle, M.D.: Research Associate, Veterans Administration Hospital, Palo Alto, Calif. N. E. Shumway, M.D.: Chief Cardiovascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, Calif. Reprint requests should be addressed to W. W. Angell, M.D., Chief Cardiovascular Surgery, Veterans Administration Hospital, 3801 Miranda A venue, Palo Alto, Calif. 94304. | 1973 by Grune & Stratton, lnc, Progress in Cardiovascular Diseases, Vol. XV, No. 6 (May/June), 1973

589

590

ANGELL, DE LANEROLLE, AND SHUMWAY

Collection Although collection of homograft valves is best accomplished under sterile conditions, logistical problems render such collection difficult, and guaranteed sterility is unreliable. 22 In almost all instances, valves are collected from routine autopsy material. Only the donor aortic valve is used. Ideally, the valves are harvested from young patients within 12 hr after death. They are examined grossly for either congenital or acquired defects. 23 A tensile strength test also may be performed on tissue in the aortic wall adjacent to the valve. 24 Under sterile conditions, the ventricular muscle and excess adventitia is dissected away from the anular attachment leaving adequate fibrous tissue at the base of each cusp. A 4-5 mm cuffof aorta is left in each sinus and above each commissural attachment. The size of the valve is measured by external dimensions avoiding the use of obturators, which may injure the leaflets or cusp endothelium. 25,~ The valve is either mounted on a support ring or left as a free graft and then sterilized.27 2~ Sterilization Histologic study of human valves following implantation indicates poor penetration of host tissue into a chemically sterilized valve leaflet. 3~ Therefore, while a chemically sterilized, tanned, or similarly treated leaflet can function well for years, it remains inert and can be expected to deteriorate eventually. 2~ In contrast, untreated leaflets examined at intervals for 4 mo to 589 yr after implantation contain fibroblasts and increased acid mucopolysaccharide ground substance. 31 Whether this represents host reaction or whether the grafted fibroblasts survive ~1 is debatable. In either case, the optimal valve would be provided by a practical method of sterilization and storage that does not damage the leaflet's collagen, elastin or fibrocytes. 2o Sterilization 32-42 has been accomplished by noxious a g e n t s such as betapropiolactone, ethylene-oxide, and mercurate. Use of tanning agents such as formalin or gluteraldehyde will also guarantee valve sterility. These techniques, however, render the valve nonviable and may have widely variable effects on the collagen, Most groups attempt to avoid these problems by sterile procurement, surface sterilization, antibiotic sterilization or irradiation. Sterile procurement is complicated, costly, and not 100% reliable. Surface sterilization has been found to be difficult, ineffective, and to cause cell death? 2 Frozen-irradiated valves are still used by Kirklin with good results. ~3 Antibiotic sterilization was first proposed by Barratt-Boyes and is the most commonly employed technique. 2~ Valves are immersed in Hank's balanced salt solution containing penicillin (50 U/ml), streptomycin (l mg/cc), kanamycin (1 mg/cc), and amphotericin B (25 U/ml), and kept at 4 ~ C for 1 wk. Ninety per cent of the valves are reported sterile at this time. R o s s 23 USeS essentially the same method. Our method, while more complex, employs the use of physiologic antibiotic concentrations for sterilizing the procured h0mograft valves. On procurement, the intact aortic valve and the three cusps from the pulmonary valve are placed in sterile tissue culture medium (TC 199; Grand Island Biological Company, Grand Island, N.Y.) The pulmonic cusps are used later for tissue culturing to check via-

PRESENT STATUS OF HOMOGRAFT VALVES

591

bility. The procurement solution is cultured to identify bacterial or fungal contamination, and any valve that gives a positive mycologic culture at this or any subsequent stage of the testing is discarded. The valves are then trimmed, mounted or left free, and washed twice in fresh, sterile TC 199. Next, the valve is immersed and incubated for 3 hr in the first solution. Solution 1 is made of 120 cc sterile TC 199 containing lincomycin (25 #g/cc), gentamicin (25 #g/cc), colistimethate (25 ~g/cc), kanamycin (25 t~g/cc), and amphotericin B (5 ~g/cc). After the valve has been incubated in Solution l for 3 hr at 37 ~ C, it is then transferred to a second solution and incubated at 37 ~ C for 21 hr. Solution 2 is composed of lincomycin (25 ug/cc), gentamicin (25/~g/cc), and amphotericin B (5 ug/cc) in 120 cc of sterile TC 199. In initial animal experiments, colistimethate and kanamycin had a rapid effect on bacteria but were quite toxic to valve fibrocytes and therefore were eliminated from Solution 2. We are still in the process of optimizing the antibiotic solution and most recently are using a single solution with lincomycin (50 #g/cc), colistimethate (25 Ftg/cc), gentamicin (25 ug/cc), and kanamycin (25 ug/cc) for sterilization. Tissue culture is the simplest and most accurate method to assess cusp viability. Tissue culture techniques vary widely, but they basically employ a tissue culture solution and a glass or plastic surface, incubation at 37~ and a controlled gas mixture. We use TC 199 with added 20% fetal calf serum, 3% glutamine, 1% antibiotic-antimycotic solution. The tissue sample to be cultured is minced, placed in a disposable, stoppered bottle containing the above solution and incubated at 37~ in the presence of ambient air. Growth of healthy animal cells occurs within 2 days, while healthy human cells grow in about 4 days. Injured cells may take as long as 2 or 3 wk to show signs of growth. We have determined viability prior to implantation and then reassessed viability after removal. There is a high degree of correlation between positive tissue cultures and the presence of viable cells histologically.44

Storage Freezing and hypothermia are logical storage methods for viable tissue. The freezing of grafts has several distinct advantages. Among these is the fact that decreasing temperature to - 1 2 0 ~ has been shown to stop all metabolic processes. This will permit storage for extended periods of time without aging of cusp cells or collagen. 4'~ This technique has been verified and is useful for the preservation of single cell suspensions such as leukocytes and spermatozoan. 46 We have been successful in maintaining viability of animal valve tissue after freezing to liquid nitrogen temperatures~ 7 Dimethylsulfoxide (DMSO), in 10% concentrations, is used as the cryophylactic agent. 48,49 Temperature is decreased at a rate of 1~C/min or slower. 45 Viability is tested by animal implantation and tissue culture and reveals that some cells are injured during thaw and reequilibration. We are presently investigating whether it is the thawing process per se or the washing out of DMSO following thawing that is most injurious to the cells. Freeze-drying has also been used for prolonged storage but both gross and microscopic damage is evident. 5~ Until such time as the freezing techniques are perfected, hypothermic storage

592

ANGELL, DE LANEROLLE, AND SHUMWAY

presents the only available method for preservation of viability. Hypothermic storage has always been our preferred method and is presently used by all groups who employ antibiotic sterilization. We store the valve in TC 199 at 12.5~ and, although there is a significant decrease in cells at 4 wk, we have found positive tissue cultures for viable cells after a maximum of 6 wk of storage. Others have stored valves in Hank's balanced salt solution at 4~ for up to 9 wk. 7,2~ While we have found hypothermic storage to be very effective for short intervals, the techniques presently used are disadvantaged by inconsistencies. Grafts stored for 3 wk are significantly different from those stored for only 1 wk? 4 The 6-wk storage limit necessitates discarding many unused grafts, making cost prohibitive and creating significant problems in procurement. The difficulty of procurement and problems in the development of consistent, nondeleterious techniques of preparation and storage have been the major factors in making the use of homograft transplants less attractive? ~ 52 Short-term hypothermic storage has served as a temporizing measure and will remain in use until better methods are developed.

Viability and Morphology The choice of a method for sterilization and storage depends on whether it is necessary to have viable cells in the graft. If it can be shown that nonviable grafts perform and function as well and as long as viable grafts, most of the sterilization and storage problems will be obviated. Although it is difficult to compare the long-term function of viable vs. nonviable homograft v a l v e s , 26'~~176 some facts are known. Chemically treated, irradiated, frozen, or freeze-dried and therefore nonviable valves develop clinically significant regurgitation at a rate of up to 5%-10%/yr. 56-58 Studies by Hudson '~9 of ethylene-oxide-sterilized and freeze-dried grafts and by Smith 3~ of beta-propiolactone-treated and freeze-dried valves show that ingrowth of host tissue has not effectively replaced or covered the nonviable cusps. The cusps remain acellular, and become focally thinned, fenestrated, torn, or ruptured. Efforts have also been made to sterilize and store valves in "tanning" agents such as formaldehyde or gluteraldehyde. This provides the simplest method of storage and may initially enhance the strength of nonviable valves. It may even lessen tbe antigenicity and susceptibility to host reactions, thus facilitating the use of heterografts2 ~ However, both animal work 3~ and clinical experience indicate that formalin-tanned valves are susceptible to attenuation with resulting insufficiency. There is also good in vitro evidence that collagen may be weakened by formalin treatment21 Gluteraldehyde is a popular, improved fixative, which obviates many of the problems with formalin. The question of whether a killed valve without host ingrowth is eventually doomed to failure remains to be answered. It is known that homograft valve grafts procured in the fresh, viable state have functioned for extended periods of time ranging from 10 16 yr. 7,~2 These grafts have been examined up to 5 yr after implantation and are noted to have living cells present histologically? 6 Cells that persist in the cusp tissue are viable fibrocytes as proven by morphologic appearance and tissue culture, Mitotic figures are seen in fibrocytes, and there is an increase in the frequency of these

PRESENT STATUS OF HOMOGRAFT VALVES

593

Fig. 1. Canine aortic homograft at 120 days. Note fibroblasts with hypertrophy, abundant granular endoplasmic reticulum, lipid droplets (round, white area, upper right) and dense bodies (black spots). Around it ere mature and immature collagen fibers. • 5,000. (By permission. ~)

Fig. 2. Comparison of fresh human aortic valve homograft at 18 mo (upper) with formalin "'tanned" pig-human aortic heterograft at 4 mo (lower). Note the increased thickness and persistent cellularity of fresh graft and the slight reduction in thickness and cellularity of " t a n n e d " valve, which has a superficial thrombus containing leukocytes. Hematoxin and eosin stain. • 32. (By permission. ~)

594

ANGELL, DE LANEROLLE, AND SHUMWAY

Fig, 3, Schematic summary of alterations in fresh homograft valves, (By permission. 26)

cells, which are better termed fibroblasts because of their enlargement and the abundance of granular endoplasmic reticulum indicative of active protein synthesis (Figs. 1 and 2). These cusp cells are morphologically distinct from host cells in that they are abnormal and dysplastic, producing a marked increase in mycopolysaccharide ground substance, We have demonstrated that donor cells actively synthesize collagen and fibrin. There are dead cells being phagocytized and others undergoing mitotic divisions. However, within 4 wk, there is a pronounced increase in mucopolysaccharide ground substance, which separates collagen fibers and fiber bundles. The lamellar pattern of collagen and elastin is disordered or replaced by disorderly whorls of new connective tissue. These proliferating fibroblasts thicken the leaflet 5-10 times normal, thereby increasing its integrity with little alteration in function. Viable donor cells are never noted in those areas of the fresh aortic homograft where stretching and attenuation of the leaflets have taken place. Host Reactions

In 40 dogs we have compared fresh valves with valves that had been stored, sterilized, frozen, or freeze-dried?6 The host and graft reactions most regularly encountered are host sheath formation above and below the graft cusp and host tissue ingrowth into the aorta and anulus (Figs. 3 and 4). 3~ The extent of

Fig. 4. Canine aortic valve homograft at 182 days. Note host sheath, fibrous thickening, persistent cellularity, and relatively intact elastic lamellae of graft cusp, Elastin van Geison stain. • 7. (By permission. ~)

PRESENT STATUS OF HOMOGRAFT VALVES

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sheathing and formation above and below the cusps varied from one graft to the next but did not differ qualitatively between viable, nonviable, frozen, and tanfied valves. The sheath never encompasses the functional cusp. Kosek says host ingrowth of the graft is variable but is also confined to the periphery and has never replaced the donor cusp tissue. Infiltration by lymphocytes, plasma cells and macrophages, hemosiderin deposits, and focal cartilagenous metaplasia characterizes this host fibrous tissue. A different opinion is expressed by John Gavin in Barratt-Boyes' group, namely, that these cells in the valve cusp are a result of rapid repopulation from the host. Although this is not tenable with our findings, the difference is as yet unresolved24

Homograft R ejection Several studies have been undertaken to detect the presence of homograft valve rejection. MohrP 5 has studied homograft valve antigenicity in both sensitized and nonsensitized dogs and found no differences in the two groups. McKenzie et al.65 replaced the mitral valve with a viable homograft and documented valve necrosis and histocyte infiltration. However, they considered these findings not to be directly related to rejection. Baue et al.66 have observed accelerated rejection in cusps placed in the subcutaneous pockets of sensitized and nonsensitized animals, but found no differences when the grafts were implanted in the pulmonary valve area. Lower 67 compared orthotopic pulmonic valve autografts with homografts and found the autografts to be thickened but otherwise normal, while the homografts were infiltrated with plasma cells and round cells. Finally, Kwong ~ found a significantly higher rate of graft survival in dogs treated with Imuran. Kosekz6 noted that most of the endothelium of fresh grafts is lost in their preparation and storage. The remainder seems to be removed shortly after implantation. Persistent cells are swollen and vacuolated or pyknotic and disrupted. Barr chromatin bodies have been identified in the cells of female-to-male valve grafts proving their donor origin. One explanation for the cell injury is that the superficial location of the endothelium makes it susceptible to physical and chemical trauma, so that it is nonviable in even the most carefully prepared fresh grafts. A second possibility is that cell injury is a hallmark of visceral homograft rejection. Alterations observed in the persisting endothelium are quite similar to those in arterial and ventricular endothelium during acute rejection of cardiac homo~rafts.6a ~ ,: In light of these observations compatible with human valve rejection, we have studied the effect of rejection on viability.69 The experimental model was a stented composite semilunar valve formed of one cusp each from a canine aortic homograft, a porcine aortic heterograft, and a pulmonic autograft. All leaflets were subject to identical preparation, handling, and hemodynamic conditions. These composite valves were implanted in 20 dogs who were sacrificed at intervals ranging from 5 days to 1 yr. After implantation for 5 days, all leaflets were slightly thickened but otherwise similar. On microscopic examination, all showed significant hypercellularity. The autograft retained its normal endothelial lining, While the homograft and heterograft lost their endothelium and showed a superficial zone of acellularity (Fig. 5).

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At 3 mo, all leaflets were grossly similar, Histologically, the autograft remained hypercellular and thickened with normal endothelium. The homograft was also hypercellular, but it exhibited fibroblastic dysplasia and discrete areas of acellularity. It contained no endothelium and had a surface composed of bare collagen. The heterograft was devoid of fibroblasts and contained areas of disordered collagen invaded by tissue macrophages and histiocytes (Fig. 6). At 1 yr, the autograft and homograft were thickened, while the heterograft was abnormally thin. The autograft remained hyperplastic with normal endothelial lining. The homograft failed to show endothelial regeneration and demonstrated fibroblastic dysplasia. The heter0graft was totally acellular with no evidence of host ingrowth into the nonviable leaflet (Fig. 7). Host rejection of the graft is difficult to assess. Its effects are slow and atypical o~ classic rejection reactions. The effect on long-term function of viable valves is probably very significant. If homografts could be made to behave like valve aUtografts, it is conceivable that a permanent replacement could be effected with a natural valve showing little morphologic alteration from the patient's own tissue.

S~rgical Technique Assurance of valvular competence is the essential feature of surgical technique with aortic homograft insertion. The two-suture-line method used by BarrattB0yes6 in 1962 made accurate insertion into the subcoronary position feasible. With proper sizing, these grafts could be used for aortic valve replacement in all but the most dilated aortic roots. Initial competence can be insured in 70%-80% of patients and nearly all regurgitation leaks are hemodynamically insignificant up to a year postoperatively. The murmur of aortic insufficiency has plagued the users of tissue valves from their inception and presently occurs in 20%-30% of p~tients receiving free aortic homografts. Early leaks are largely technical in origin, usually as a result of less than the ideal 4-5 mm of central coaptation of valve leaflets. Slight malposition from any cause may result in a central valve leak due to imbalance of this critical coaptation. With healing-in of the graft, the distortion tends to be exaggerated, and small leaks may then appear or be increased if already present. The same phenomenon results from dilatation of the recipient's aortic root following insertion of a free graft. Any homograft reaction of the donor cells tends to increase leaflet thickness arid while this results in increased valvular integrity, it may also aggravate critical disparity of leaflet coaptation. This accounts for the observation that inert grafts will result in fewer initial changes than the more reactive fresh grafts. It is important to separate aortic insufficiency secondary to this phenomenon of poor leaflet coaptation from regurgitation seen with leaflet disruption resulting in dehiscence or fenestration. The former problem, being technical and mechanical in nature, lends itself to simpler solutions than solving the major difficulties secondary to leaflet deterioration. The initial technique of aortic valve replacement of the free homograft has persisted with a few modifications, although experience has resulted in a method that can now be employed with an impressive degree of flexibility and facility. We estimate insertion time at 10 min longer than the single suture line technique of

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prosthetic valve insertion. This is a difference that is statistically insignificant when related to morbidity and mortality. Unfortunately, the two-suture-line free homograft insertion is dissimilar to standard valve replacement methods. This can create problems in the hands of teams not familiar with the technique and has prompted some interest in the use of premounted valves. As described under Collection, premounting can be done shortly after procurement by a technician in the laboratory, obviating many of the problems of intraoperative valve orientation. Premounted valves use the same double suture-line method, securing the graft to a rigid or semirigid support ring. The ring support and valve are then inserted, using the standard sewing ring cuff method employed for prosthetics. These premounted valves have the obvious advantages of simplified insertion and precalculated coaptation and competence. They have been used in all intracardiac positions. Premounting has two significant disadvantages in that it insinuates a barrier between the valve and host, which depends a great deal on the persistent suture material, and prevents host ingrowth into the valve anulus and supporting aorta. The ring also lacks the normal flexibility of the aortic root and may therefore increase the abnormal stresses on the valve leaflet mechanism. While neither has proven to be a significant problem to date, the method is new, and long-term effects are not well defined. The fresh aortic homograft freely sewn into the subcoronary position is a standardized method, which has been in use for 10 yr. It is still used in essentially the same manner as at its inception. This technique has the lowest reported incidence of valve related complications, and the longevity record is one that is unparalleled by valve replacement of other types whether they be prosthetic or biologic tissue. Clinical R esults Statistical evaluation of clinical results is essential to an accurate assessment of valve function. Traditionally, results have been reported in terms of overall mortality or morbidity. It is not sufficient, however, to report flat percentages of deaths and complications as these figures are meaningful only in the context of duration of patient follow-up. In other words, it is essential to evaluate valve survival as an expression of patient morbidity over a specific postoperative interval. The method of actuarial analysis reported for follow-up of cancer patients 7~ is now the accepted standard for reporting follow-up of valve patients. It reports only those patients followed for a specific period and the percentage incidence of death, complichtions or valve function in that group for that interval. It has the disadvantage of decreasing accuracy due to the decreasing number of patients as the interval of follow-up becomes longer. In the following comparison of results with homograft valves, we have referenced and indicated much of the nonactuarial data in addenda or footnotes in order to clarify the discussion. We refer in the text only to those figures which are available on an actuarial basis. Aortic Hornografts There are four groups who have significant experience and an ongoing interest in the use of human homograft valves for aortic valve replacement. They are Brian Barratt-Boyes at Green Lane Hospital, Auckland, New Zealand;

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Results of variably treated aortic valve homografts from Ross (259 patients). BarrattBoyes (490 chemically and 16 antibioticsterilized valves), Kirklin (187 patients), and Angell (189 patients). (By permission of The American Heart Association, Inc., 4~ and J. Thorac. Cardiovasc. Surg. 44)

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Donald Ross at National Heart Hospital in London; John Kirklin, whose experience began at the Mayo Clinic and has continued at the University of Alabama Hospitals in Birmingham; and William Angell and Norman Shumway at Stanford, California. Figure 8 shows the results of aortic valve replacement from these four groups. The overall survival rates are not truly comparable, as some of the series (Birmingham and Stanford) are highly selected groups of patients, while others (Auckland) include virtually all patients operated on over the interval. At present, hospital mortality is similar for all four groups. Gonzalez-Lavin and Ross7] have reported on 259 patients who received aortic valve homografts over a 5-yr period. The majority of the patients reviewed had valves sterilized by ethylene-oxide and preserved by freeze-drying. Most of their long-term results relate to these patients.* The 212 patients discharged from the hospital have been followed from 189 to 789yr. Exclusive of hospital deaths, the actuarial survival rate of these patients is 72% at 5 yr, with less than one-half of these deaths being valve related. Excluding hospital deaths, the actuarial survival at 4 yr was 90% for patients operated on in 1967, as opposed to 75% for those operated on in 1965, showing a persistent and dramatic improvement with each succeeding study year. The incidence of valve failure has also decreased with increasing experience with homografts.t Gonzalez-Lavin and Ross considered degenerative changes such as calcification and cusp rupture to be caused by the method of sterilization and preservation. Significantly, they have recently switched from killed valves to fresh, antibiotic-sterilized valves. Twenty-three of these patients have been followed up to 2 yr, and 20 of them have competent valves. The other three have only trivial aortic regurgitation characterized by soft, short, diastolic murmurs. Barratt-Boyes has recently reviewed his experience during 9 yr of homograft valve transplantation.7 The aortic valve replacement group was divided into chemically treated and fresh valves. Since late 1962, chemically treated homograft valves have been inserted in 490 patients.~ The 6-yr actuarial survival rate is 69%, which does take into account 56 patients who were operated upon a second time, 20 of whom died either during or after the second operation. Although the actuarial incidence of valve failure is not reported, essentially all valve regurgitation was due to valve failure. Leaflet rupture remains the major *Ross: hospital mortality 16.6% initially; declined to 4.8% in the past 2 yr. tRoss: 71% of patients retain their original valves with an overall valve failure rate of 18 %. Barratt-Boyes: chemical sterilization-+ 8% hospital mortality rate; overall valve failure rate, 13%,

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problem with the chemically treated valve, with stenosis from leaflet calcification and endocarditis relatively rare occurrences. Of the 16 patients in Barratt-Boyes' series who received fresh, sterilely procured valves in 1962, 79% are reported alive 9 yr after operation. Four have required a second operation for valve incompetence 1, 3, 5, and 9 yr after implantation. Two died 4 and 16 mo after surgery, while the other 10 (62%) have the original valves in position. Two of these patients have moderate incompetence. Only one patient demonstrated a progressive increase in the degree of incompetence as compared with the findings I yr after operation. Six underwent cardiac catheterization 5 yr after surgery--valves were competent and gradients measured 4 15 mm of mercury. Because of the problems with chemically sterilized valves and the good results from this initial series, Barratt-Boyes initiated an antibiotic sterilization technique as described under Sterilization. A total of 230 patients who had isolated aortic valve replacement with antibioticsterilized valves* now have been followed up to 3 yr. Kirklin and his associates report an overall 389 yr actuarial survival rate of 93.5 % in 187 patients undergoing aortic valve replacement with frozen-irradiated aortic homografts. This group represents a selected case series with the mean patient age being approximately 43.8 yr and the elimination of all patients with marked aortic root dilatation. Moderate or severe valvular incompetencet in the form of central leaks without cusp perforation is felt to be due to improper technique of insertion or poor matching of homograft and aortic root size. Thromboembolic complications were not observed, and only one instance of infection is reported. At present, they prefer homografts for patients in whom they can be used without tailoring the aortic root. 43 Our experience44 (Figs. 8 and 9) with homograft valves has been in the form of 426 patients receiving homograft valves in all intracardiac positions. There have been 189 isolated aortic replacements that have been followed for 5 yr.:~ Over the 5-yr experience, our emphasis has been on use of fresh valves. At first, valves 100

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were procured under sterile conditions and subsequently sterilized by antibiotics with frequent checks to determine cell viability. Young patients were initially selected, but in the past 3 yr the series has been essentially consecutive. There have been 189 isolated aortic replacements with a 5-yr survival of 80%. Half of these deaths are accounted for by valve-related causes. We have computed the significant valve-related complications as a percentage of living patients on an actuarial basis. Seventy per cent of the patients who are alive have grafts that are functioning wel'l without suffering any serious problems. Valve-related complications include all infections, significant regurgitation, and reoperations.

Mitral Homografts Two groups (Auckland and Stanford) have been involved in mitral valve replacement with the use of homograft valves. We have replaced the mitral valve in 203 patients over a 5-yr period. 44,72 While the mortality rate compares quite favorably with theluse of these grafts in the aortic position, the complication rate in patients with mitral homografts is significantly higher. Only half the patients operated on 5 yr~ ago have valves that are functioning well and have not suffered a significant complication or reoperation. This undoubtedly reflects the increased in vivo trauma and stress placed on the tissue valve in the atrioventricular position.

Homograft vs. Starr-Edwards Aortic Valve Replacement Figure 10 shows the comparative results of two series of matched homograft vs. Starr-Edwards valves as presented by the Birmingham and Stanford groups. The Birmingham series of homograft patients is matched with a like number of Dr. Albert Starr's patients of similar mean age (43.8 yr) who had received a Starr-Edwards model 1200-1260 series ball valve prosthesis. The greatest difference between the slopes of these two survival curves occurs during the first 2 postoperative yr. Similarly, we have matched a group of patients from the Stanford Starr-Edwards experience. The only significant difference in these curves appears in the last year when only 14 patients were available for follow-up. While this comparison of statistics suggests we are using valves which are less than ideal, it indicates t'hat the free aortic homograft carries a mortality rate that is no higher than that for prosthetic valve replacement. 100

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ANGELL DE LANEROLLE, AND SHUMWAY

Summary All of the groups mentioned have turned to the least traumatic method of valve preparation. Antibiotic sterilization is used by all except Kirklin, whose excellent clinical results have prompted him to continue the use of irradiated frozen valves. Chemically treated valves have been continually plagued by regurgitation, making it essential to separate out the fresh aortic homograft from other types of tissue valves. This is particularly important as there has been a common clinical impression that the percentage and severity of homograft regurgitation is far greater than the incidence of complications secondary to prosthetic valve replacement. It is essential to separate fresh from attenuated homografts when evaluating the limited actuarial data available (Fig. 8). It is also imperative to insist on accurate actuarial reporting of all types of valve results. Only in this way will comparative results between types of valves used in different medical centers be meaningful and lend themselves to logical evaluation. PROSTHETIC VALVES

In 1954, HufnageF~ reported the insertion of a caged-ball prosthesis in the descending aorta of 23 patients with pure aortic insufficiency. Seventeen of these patients survived and improved. Although it was believed at the time that up to 75% of the aortic regurgitation was controlled by this technique, it was recognized that the site used was not the optimal position for implantation. Subsequent experience74,75 has indicated that the physiologic improvement was not as great as anticipated and that decreased diastolic pressure at the coronary orifice was responsible for increased angina experienced by many of the survivors. Other reported complications include subacute bacterial endocarditis, myocardial failure, and thromboembolism.76,77 The first successful replacement of the aortic valve with a caged-ball prosthesis implanted in the subcoronary position was achieved by Harken in 1960.78 The first mitral valve replacement with a caged-ball prosthesis was performed by Starr, 79-sl also in 1960. Early experience with the caged-ball prosthesis demonstrated that the hemodynamic principle was basically sound? 2,83 These valves have the additional advantages of simplicity of construction, ease of insertion, and availability in a large range of sizes for both mitral and aortic replacements. The principal disadvantages, in order of increasing importance, are hemolysis, infection, mechanical failure of varying types, and thromboembolism. Intravascular hemolysis following aortic valve replacement was first reported by DeCesare. 84 The appearance of anemia in the three patients coincided with the development of severe, late, postoperative aortic insufficiency. Such perivalvular leaks have been implicated as the cause of increased turbulence in a high percentage of patients with severe anemia after valve replacement. Studies by Wallace8'~ have indicated slightly elevated rates of heme catabolism in patients with normally functioning prostheses, accounting for the observation that predisposing hemolytic anemias are nearly always aggravated by valve replacement. However, the precise incidence of hemolysis is not known, although Start ~6 has reported a 15% incidence of hemolysis in patients receiving aortic prostheses. A more recent study covering his newer models has yielded similar results? 7

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605

Prosthetic valvular infection is also a well-known complication. During the developmental stages of cardiac surgery, the reported incidence of bacterial endocarditis varied from 3%-10% 88,89 and was noted to be a function of cardiopulmonary bypass--which carried a fourfold risk of infection. 9~ Opinion regarding prophylactic chemotherapy has been controversiaW and valid data from carefully controlled double-blind studies have been difficult to obtain. 94 General consensus is toward the use of prophylactic antibiotics instituted prior to surgery and continued for at least 10 days? s,~6 There is also a low incidence of endocarditis in and about the valve following prosthetic replacement. This seems to occur at a rate of less than 1% per yr of follow-up regardless of valve type used. 97 The best treatment for such infection is valve removal and replacement early in the course of the disease. In early experience, concern about the durability of caged-ball prostheses has Centered on ball variance, which is defined as valvular dysfunction resulting from physical and chemical alteration in the ball of the prosthesis. Incipient ball variance is discoloration due to lipid infiltration, swelling, and decreased elasticity of the poppet, each of which may be present without mechanical dysfunction of the valve. Fatal escape of the balW ,9~ has been reported but is a relatively rare occurrence. Particulate embolization has also been reported? ~176 Other alterations occurring in silastic balls include increased diameter with impingement or sticking on the cage struts, grooving, cracking, and impingement of the ball against the wall without swelling. All of these changes are potentially fatal. 1ol The basic mechanism underlying ball variance seems to be infiltration into the ball of a complex, polar, lipid substance that is not specifically identifiable. Infiltration is followed by swelling, softening or cracking, or all three. Increases in weight and volume have been noted, but the mechanism is unclear. 1~ In cases he has reviewed, Start has noted that abnormalities of implantation possibly cause greater than normal stress or trauma to the ball. '~ It has also been suggested that ball variance may he a function of the degree of cure and the amount of silicone dioxide filler added to the stock used for making balls. '~ The incidence of this phenomenon has been reduced and may be eliminated by the change in silicone cure of earlier models or by use of hollow Stellite balls in newer models. Perhaps of greater concern today is the question of what mechanical failures will occur as a result of very long-term function. The problems of fabric wear and tissue ingrowth and overgrowth have also been noted and may create as many problems as they alleviate."" Thromboembolism, of all the complications reported from the use of prosthetic valves, has been the most frequent. The reported incidence of thromboembolism~O6 ,,o has ranged from 8.4%-24.7% in patients receiving the early model Start-Edwards aortic prostheses (1000 and 1200 series). The incidence has been somewhat higher (22.9%-32.4%) with the Magovern prosthesis? ~176 The best long-term follow-up results have been obtained from the Smeloff-Cutter prosthesis 1'1 with the incidence of thromboembolism ranging between 2.5% and 5% in SmelotVs 1'~ and Cooley's '~ patients. Recent reports of clinical trials based on experimental work by Dr. Nina Braunwald have established that total fabric

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encapsulation of the prosthetic cage with a porous fabric encourages the development of an autologous tissue covering and decreases the incidence of thromboembolic complications.'13-124 As a result of these observations by Braunwald, the Cutter 118 and StarrEdwards 12'5 prostheses were modified and the existing cages totally covered with knitted Teflon. Unfortunately, some of these changes had adverse hemodynamic consequences '26 and the Starr-Edwards model 2300 valve was remodified to produce the model 2310 prosthesis. 127 A recent evaluation of 169 patients undergoing aortic valve replacement with the model 2310 indicates no early emboli and only two late emboli in 1976 patient-months of follow-up. 12~ As a result of 4 5 yrs' work at the N I H , Braunwald and her co-workers have developed an open-ended, caged-ball valve that has a poppet made of silicone elastomer that has been treated with the mild-cure technique? ~8 An ultra-thin polypropelene fabric mesh is used to cover the inflow orifice and a single layer of porous Dacron fabric tubing is used to cover the struts. This valve is reported to have lower gradients than the cloth-covered Starr-Edwards 2300 aortic and 6300 mitral valve series. Also, it does not seem to have the problem of ball-sticking and fabric wear noted with the newer model Starr-Edwards valves. 1'8 This valve has now been used clinically for mitral and/or aortic valve replacement in 32 patients. These patients have been followed for up to 20 mo, and there has been no evidence of thromboembolic complications. '29 In the past few years, some new types of prostheses have appeared on the market along with the nonthrombogenic valves. Among these have been the hingeless, tilting or disc, low profile, high flow orifice valves that were first introduced by Wada 13~ and popularized by Bjrrk and Lillehei. These valves have great applicability as mitral valve replacements as they occupy little space and do not protrude into the ventricle as the ball valves do. Kay-Suzuki TM and Beal1132 valves are amor.g the disc poppet valves that have enjoyed significant intervals of clinical use. The BjiSrk-Shiley tilting disc valve 'aa has been inserted in one series of patients with a 7.5% primary mortality rate (all of the deaths were reportedly unrelated to the valve) and no late deaths in a 6 15 mo follow-up. All patients were anticoagulated and there were only two cases of emboli in the 74 surviving aortic valve patients. Messmer and Cooley have reported a slightly higher mortality rate (9%) and a similar incidence of emboli in 100 patients receiving the Bj0rk-Shiley valve. TM However, in the overall experience, disc valves have been plagued by technical difficulties and mechanical failure. Many of these problems are apparently due to altered flow patterns and interference with the disc by tissue ingrowth? a5 The operative mortality for isolated aortic valve replacements with prosthetic valves has ranged between 4% and 16%.a7,136,137 The lower figure represents mortality in the recent years as experience with surgery and postoperative care has increased. '37 Operative mortality for mitral valve replacements in patients with no prior cardiac surgery has been reported to be as high as 23%? 3~ When evaluated by the actuarial method, 7~ the Mayo Clinic reports 70% survival 4 yr after aortic valve surgery. Aston '36 reports 50% survival 6 yr following aortic valve replacement and 25% survival 6 yr following rnitral valve replacement. Cooley 1~ reported in 1969 on 946 patients undergoing aortic valve replacement

PRESENT STATUS OF HOMOGRAFT VALVES

607

between 1962 and the end of 1968. The overall mortality rate was 11.6% and the long-term survival, although not analyzed by the actuarial method, was indicated to be 55% at 5 yr. Late thromboembolic complications occurred at a rate of 12.2% in all patients. The incidence of emboli with different valves was as follows: Starr-Edwards, 24.7%; Magovern prosthesis, 32.4%; and Smeloff-Cutter valve, 4.9%. Mechanical complications have occurred in 8.8% of the patients surviving surgery; over 50% of the mechanical failures were due to detached valves. More recently, Sutherland '3s has reported on 1571 valve replacements taking place in Australia between 1962 and June 1969. There were 752 aortic valve replacements and 622 mitral replacements with Start-Edwards valves. Operative and hospital mortality was 16% in both groups. Actuarial curve analysis showed a 6-yr survival rate of about 55% for both mitral and aortic replacements. There was a 3.7% infection rate in those surviving valve replacement, with most of the infections recorded in the first postoperative yr. Dehiscence or serious perivascular leaks and ball variance were present in about 6% of the survivors. Actuarial analysis of thromboemboli showed 43% and 66% incidence of thrombi in aortic and mitral valve patients, respectively, by the sixth yr. Starr and his co-workers ,zs have reported on 121 patients undergoing isolated aortic valve replacement and 48 patients undergoing multiple valve replacements with the composite seat cloth-covered model 2310 prosthesis. The operative mortality rates were 13% and 15% in the two groups, respectively. The surviving patients were followed from 1-3 yr. Despite the fact that some of the patients are not taking anticoagulants, there have been only two possible embolic complications during 1976 patient-months of follow-up. Both of these patients had double valve replacements. Orifice cloth tear, cloth wear, hemolysis and anemia, and ball-sticking have all been significant problems associated with this valve. These causes of valve deterioration do not yet have a reported incidence, probably due to the short period of follow-up. Finally, Spencer and his associates have reported '2~ on 267 patients receiving various model Starr-Edwards prostheses in the aortic, mitral, and tricuspid positions. One-hundred-and-nineteen patients received isolated aortic valve replacements. The operative mortality was 4.2%. Actuarial analysis shows a 75% survival rate almost 5 yr after isolated aortic replacement. There was a total 4% incidence of emboli in all 267 patients. Only 0.7% were fatal. However, most of the embolic episodes occurred after anticoagulation therapy was discontinued. On the other hand, anticoagulation has, in itself, been hazardous, and prosthetic infections (3.4%), hemolysis, cloth wear, and valve dehiscence have all been noted. HETEROGRAFT VALVES

Due to the inherent problems associated with the use of human aortic valves, investigators have sought other sources of suitable valve grafts. Heterograft valves have proved an attractive possibility, as they are available in unlimited numbers and sizes. Duran and Gunning ~4~ first implanted heterograft aortic valves in the descending aortas of dogs in 1965. This technique was modified for clinical use by Binet? 39 Data from many other investigators covering almost 5 yr of clinical trial are now available. '4~

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Morphologically, heterograft valves, like human aortic valves, have asymmetrical leaflets. In the calf, one cusp is larger than the other two, while in other animals the noncoronary cusp is more shallow. 14~ The cusps are also more cellular than human cusps. H'~ Another difference between human and heterograft valves is that the heterograft valves have somewhat more myocardial tissue supporting coronary sinuses, 146 making preparation of these valves more difficult. In designing a method for heterograft preservation, the following criteria must be met: guaranteed sterility, preservation of strength and flexibility, attenuation of immunologic reaction, and prevention of long-term denaturation of collagen. 147 Initially, Binet ~'~9 sterilized his valves by immersion in a mercurial salt solution. Although this technique gave some good results, infiltration by inflammatory cells, and by immunologically competent cells, and denaturation of collagen were found in valves removed because of failure. 148 O'Brien 14~ then used a previously described technique of curing valves in a 4% formalin solution buffered to a pH of 5.6. With free graft aortic replacement, this method gave initially good results in patients for up to 4 yr. Since then the failure rate has approached almost 50%. ~4d The tissue thins, stretches, deteriorates, and eventually tears or fenestrates with resultant insufficiency. Histologically, although there is some infiltration, host tissue has never been observed to invade the functional cusp of an acellular valve. Attenuation of the collagen itself is inconsistent and is dependent on how long the valve is preserved in formalin. 15~ Carpentier has outlined a method of curing and preserving heterograft valves using gluteraldehyde. 147'145 After the valve is removed from the heart, it is placed in Hank's solution and constantly stirred for 2 hr. This removes the soluble pro2 teins. Then the valve is trimmed, and if desired, mounted. During this procedure the valve must be continually dipped in Hank's solution to prevent dehydration. Next, the valve is placed in a solution of sodium metaperiodate for 24 hr at 40 ~C: The sodium metaperiodate has the effect of creating free aldehyde groups at the end of the telopeptides extending from the mucopolysaccharide and glycoprotein molecules, denaturing these molecules by oxidation. These free aldehyde groups spontaneously cross-link with free amino groups of adjacent molecules forming irreversible cross-links. The valve is then placed in a solution of ethylene-glycol for I hr with constant stirring to neutralize the effects of the sodium periodate. Finally, the valve is placed in a solution of gluteraldehyde, in which it can be stored for several months at 4~ The gluteraldehyde binds the free amino groups, thereby theoretically removing almost all the antigenic factors by binding or cross-linking, and increasing the stability of the collagen by cross-linkage to different molecules. Of the initial series of patients in whom Binet implanted heterografts treated by the mercurial salt method, only 33% had survived when reported in 1969. 34 Twenty per cent of these patients required reoperation to replace insufficienl~ valves. In a later series of 27 aortic valve replacements using mounted heterografts cured by the method of O'Brien, there were only five hospital and late deaths. There were no thromboembolic episodes despite not using anticoagulants. O'Brien has subsequently reported on 129 patients receiving composite heterograft valves made by using three noncoronary cusps. ~9,~51 Such a valve is

PRESENT STATUS OF HOMOGRAFT VALVES

609

symmetrical and has the advantage of being constructed with a cusp that is not attached to ventricular muscle. Of the 129 patients, 100 had aortic valve replacements, 19 mitral, and 6 multiple; 4 had replacement of incompetent ball valves. The overall mortality for this group of patients was 8% with a sharp reduction in the last 50 cases. Four yr of follow-up showed no incidence of thromboembolism or endocarditis. One of the late deaths and one reoperation were due to valve deterioration. Aortic incompetence was clinically severe in three additional patients and moderate in 18 others. Due to the frequency of incompetence, O'Brien has gone to the use of fresh aortic homografts, gluteraldehyde fixed heterografts and fascial autografts. Carpentier '47 has reported on 53 patients receiving heterograft valves treated by three different techniques. Incompetence necessitated graft removal in nine patients. In five patients incompetence was due to technical error, and in four patients, biologic tissue alterations were the cause of failure. These grafts were removed from 3 mo to 3 yr after implantation. Host reactions were found to be the cause of graft failure in five patients. Degenerative changes appeared in the adjacent collagen and elastin fibers. Both immunologically competent cells and inflammatory cells were concentrated in the graft sleeve, either in the region of the host interface or along the suture line. The holes created by the sutures seemed to facilitate cell ingrowth. Denaturation of collagen and elastin without cell infiltration was observed in three cases. Generally, the cusps appeared eosinophilic and amorphous. In all cases, the general architecture of the valve was changed and the elastic fibers were disintegrated. No calcification was observed. It was Dr. Carpentier's conclusion that preservation and pretreatment were the most important factors affecting their long-term fate. Subsequently, he has found only two cases of graft failure in 35 patients who received gluteraldehyde-preserved valves over a 1-5-yr period. '52 Recently, Ionescu et al. ~'~3 have reported on 87 patients receiving aortic heterograft valves. There were 70 operative survivors, of whom 19 have had failing grafts and 7 have had major complications not related to the valve per se. Some of the grafts were sterilized using the beta-propiolactone and freeze-drying method, '~ which proved to have deleterious side effects. Sterilization in 4% buffered acid-formaldehyde 14~ proved a good method, but the tanning effects of formaldehyde are weak and seem to provide only temporary cross-linkage of the protein chains. They feel that formaldehyde does not prevent host-immune reactions, and express doubt that the antigenic potential is attenuated. The combination of cellular infiltration and extensive changes in connective tissue and ground substances, along with failure of the endothelium, suggested to Ionescu that the pig heterograft valve became a mechanically vulnerable structure in the process of host reaction. It was his opinion that the low durability of the formaldehyde-preserved graft, the unacceptable number of graft failures, and the unpredictability of failure made these grafts impracticable for clinical use. Our clinical experience '5~ with heterograft valves is in the form of 32 formalintreated grafts implanted over a 9-mo period. There were 10 aortic, 16 mitral and 3 double valve replacements. The overall mortality was 9.4%. All valves functioned well initially, and there were no insufficiency murmurs at the time of discharge. Anticoagulants were discontinued 4-6 wk after surgery. All but four

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grafts have failed from 2 mo to 4 yr postoperatively. All were announced by the onset of easily detectable insufficiency murmurs. Prior to the time of failure, the patients had excellent valve function with minimal or no valve gradients and insufficiency. There have been no thromboembolic phenomena or endocarditis in the follow-up period of 48 too. All valves removed showed diffuse deterioration with thinned, stretched, and weakened leaflets. Insufficiency was most commonly due to commissural tears, although there were occasional tears in the leaflets at the coaptation point (Fig. 11). O'Brien has suggested 149 that degeneration may take place due to handling of the valve prior to implantation and suggested not touching the leaflets during preparation. However, the changes we have seen cannot be attributed to technical failure, including handling, alone. Many areas of these valves were thinned to the point of transparency and the tissue strength was profoundly reduced. There was no residual evidence of formalin fixation. Microscopically, the leaflets were acellular and showed tissue invasion by host macrophages. Electron microscopy revealed these macrophages to be actively phagocytizing collagen and elastin (Fig. 12). In all specimens the base of the cusp had a superficial sheath of host tissue that consisted of a streaming of host fibroblasts to a distance of 3-4 mm along the leaflet surface (Fig. 13). These cells did not appear to be invading the interior portions of the leaflets and could not be construed as ingrowth. A single specimen revealed unequivocal evidence of host fibroblastic ingrowth into the leaflet substance. This process extended one-third of the total cusp length and abruptly ceased. This was present in one cusp only while the other cusps of the same valve showed the usual sheathing effect (Fig. 14). These clinical results indicate that treatment of heterograft valves with 4% formalin results in excellent early function. We have found that the tanning effects of formalin can be heightened by increasing the concentration of formalin, the temperature of storage, or the hydrogen ion concentration. After implantation, there is a return of formalinized tissue to a more normal gross state, and increased tanning does not eliminate this reversal. The unpredictable nature of formalin fixation and the high incidence of valve failure have cautioned us in the clinical use of heterograft valves. We have, however, had a good experience with six patients who received gluteraldehyde-treated valves 2 yr ago. There are no valve failures, which is in keeping with the experience of others who are using commercially available gluteraldehyde-treated heterograft valves. We should

Fig. 1 1. Deteriorated heterograft leaflet torn at coaptation point. (By permission. ~5~

Fig.

12.

Macrophage in aortic valve host macrophages with phagocytosis of elastin (el) and collagen fibrils (f). • 3,750, (By permission. ~5~

heterograft.

Note

Fig, 13. Superficial layer of host tissue on the base of the cusp. (By permission. '~'~

Fig. 14. Host ingrowth into heterograft. (By permission. ,,~o) 611

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ANGELL, DE LANEROLLE, AND SHUMWAY

caution that in animal experiments we have noted late deterioration similar to that seen with formalin when the valves have been removed 1-2 yr after implantation. FASCIA

LATA REPLACEMENT

Senning reported in 1967 on the use of autologous fascia lata tissue for the replacement of aortic valves. 154,~'~'~ Fascia lata has the advantage of being autologous tissue that is available at any time, and which can be fashioned into virtually any valve size. In these early papers, Senning reported a 14.4% hospital mortality rate in 90 patients who had aortic valve replacements. There were ten late deaths from 3-52 mo postoperatively. Half of these deaths were from subacute bacterial endocarditis. At the time of publication, the patients had been followed for up to 52 mo without showing any great dysfunction. 155 Encouraged by these results and those of EdwardsJ 56,l.~7 other centers began clinical use of fascia lata valves.158,159 The fascia lata for the valve construction can be mounted on a support ring 16~ ~ or implanted as a free graft? '~ A precise surgical technique for implanting supported or unsupported valves was developed by Ionescu '64 and Gonzalez-Lavin and Ross? 3 Ross has reported the results from 142 patients who had fascia lata valves implanted in the aortic position 2a and 47 with mitral valve replacements? 6a Hospital mortality was 7.4% for aortic valve replacement and 17% for combined replacement. Systemic thromboembolism was not encountered despite cessation of anticoagulation after the third postoperative wk. Ross, like IonescuJ 64 has encountered a relatively high incidence of infection. Of his 142 aortic valve patients, four had infection at the site of the fascial graft; three developed bacterial endocarditis; and two others developed septicemia. The latter five died from their infections. Ionescu "~4 has reported an 8.8% incidence of infective endocarditis, which was the cause of 6.3% of all deaths. It appears that these fascial grafts are either more vulnerable to infection 165,166 or are inadequately sterilized. It has been reported by Ionescu that the postoperative t r e a t m e n t of patients with ampicillin-cloxacillin has decreased infective endocarditis. 164,~7 The incidence of valve failure due to progressively worsening regurgitation has been prohibitively high, particularly with mitral valve replacement. Ionescu has reported valve failure in 5 out of 87 patients surviving operations in which the mitral valve was replaced? 68 In each of these patients, progressive regurgitation was caused by retraction of one or two of the cusps. Other authors who have had similar results t52,'54,158,'60 point out that this incompetence may be due to the use of valves that have variable opening and closing characteristics due to imperfect construction. 164 The significance of fascia viability has not been determined. There is evidence that the stained nuclei visible on the surface and between the collagen fibers in the removed fascia lata valves are invading, potentially active host cells? 7~ Furthermore, construction of the valve in the operating room during surgery is not optimal timewise, and therefore Ionescu has replaced autologous fascia lata with homologous fascia lata. The homologous fascia lata has, in turn, been replaced by heterologous pericardium because of its thinness and pliability. 164 These valves are sterilized by the previously described method of Carpentier and Dubost? '~2 As with all nonviable grafts, the durability of the valve is not dependent on regeneration by the host cells but on the stability of the graft tissue.

PRESENT STATUS OF HOMOGRAFT VALVES

613

Recently, Ross has published another report on his experiences with 262 fascia lata valves implanted in 201 patients? 7~ The common mechanism for failure in all supported fascial valves implanted in the mitral position was found to be regurgitation due to thickening and retraction of two of the cusps with partial fusion of the common commissure. There was less regurgitation and failure of valves implanted in the aortic position, but these valves had a higher incidence of bacterial endocarditis. He concluded that the accurate construction of the valve is imperative as the slightest asymmetry of the cusps has significant hemodynamic consequences, and that the position of implantation plays a significant role in the function or malfunction of the valve. Ross encountered his best results with fascia lata valves in the aortic position, but due to the discouraging results obtained with pulmonary, ~Tz tricuspid, and mitraU' implants, he has suspended the use of living fascia lata grafts as valve substitutes. Ross' experience is generally representative of other investigators using fascia lata valves. Most now recommend use only as free grafts in the aortic position and only on the basis of clinical trial of an unproven technique. PU LMONARY AUTOGRAFTS Attention has been given to the use of autologous tissue for valve substitution, particularly in the aortic position. Experimental work 67,17:~has demonstrated that it is possible to use autologous pulmonic valves as a substitute for aortic and mitral valves. Such a procedure has obvious advantages in that the pulmonic valve is composed of living tissue, is procured sterile just prior to implantation, does not have to be stored, and is not rejected. In 1967, Ross ~74 reported on the clinical use of pulmonary valve autografts and, at last report, ~:~ 105 patients had undergone such a procedure. Hospital mortality was 12.4% or 13 out of 105 patients. Refinements in the surgical technique and improvements in the postoperative care have decreased the hospital mortality. Only five of the last 69 patients operated on died (7.2%) in the hospital, a reduction of 5.2%. Ninety-two per cent of the patients surviving the surgery were alive and well? a In that report, the follow-up period ranged from less than 1 yr to 3 yr and 7 too. Ninety-eight per cent of the surviving patients are asymptomatic, and there was no incidence of thromboembolism, although no anticoagulants were used. The appearance of diastolic murmurs followed the same pattern as homograft valves TM but at a lower incidence. ~75 Four grafts were removed at 1-day, 1-, 13-, and 15-too intervals. Aortic regurgitation was found to be due to malposition. The leaflets of the valves appeared thin, pliable, and intact. Ross ~7'~ has reported that histologic sections of these cusps revealed normal architecture of the cells and collagen fibers indicating normal living structures. While this procedure has merit in certain cases, the complexity of removing and replacing the pulmonic valve as well as implantation in the subcoronary position limits its usefulness.

CRITICAL EVALUATION OF DIFFERENT VALVE TYPES

One question becomes of paramount importance in evaluating homograft valves: "What is the rationale for the continued use of homografts in light of the

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generally good results from valve replacement with prosthetics?" One must identify specific indications for, or advantages of, tissue valves in order to justify their continued clinical use. A comparison of valve types should be based primarily on the basis of longevity and the valve-related complication rate. McGoon ~76 established a set of guidelines for comparing grafts and prosthetics for valvular replacement.

A vailability and Choice of Size One of the greatest advantages of prosthetic valves is their availability in a large range of sizes. Heterografts can also be obtained and stored prior to surgery and are essentially as convenient as the prosthetic. Perhaps the greatest disadvantage associated with homograft usage is their lack of ready availability. The logistical problems of acquiring, sterilizing and preserving viable valves are intimidating. If viability proves unimportant or if preservation techniques are perfected to permit long-term storage of viable valves, it would be difficult but possible to establish valve banks that could provide valves of specific size on request.

Ease of lnsertion Here again the prosthetics enjoy a decided advantage. They can be inserted more easily and rapidly than the free-sewn biologic valves. Use of framemounted homografts or heterografts eliminates this differential. These premounted grafts must be carefully oriented and sutured so as to insure adequate coaptation and competence. The commercial availability of heterografts and the improved results with premounted homografts indicate that the problems formerly associated with premounting of tissue valves are surmountable.

Durability and Valve Survival Ball valves have been shown to have a good record in terms of valve survival, since some have functioned well for over 7 yr in some patients. There have been reports of ball variance, ball-sticking, and ball escape, but these phenomena have been relatively rare. The newer cloth-covered valves present some problems with durability due to cloth wear and tear as well as tissue ingrowth and overgrowth. The relatively short duration of follow-up makes it difficult to determine the severity of this problem. The fascia lata, formalin-cured heterografts and chemically sterilized homografts are the least durable of the biologic valves. Gluteraldehyde-cured heterografts may be considerably more durable but cannot yet be assessed in terms of long-term usage. Homografts, particularly fresh or viable valves, have been shown to function well for more than 10 yr and functional cusp mobility has been demonstrated after 16 yrs' implantation in the descending aorta. Procurement and storage problems often manifest themselves as valve failure because tissue that is not ideal from the standpoint of age, integrity, and size has been used. Advances in valve preparation and storage techniques as well as implantation methods have, therefore, resulted in impressive improvements in valve survival data.

PRESENT STATUS OF HOMOGRAFT VALVES

615

Hemodynamic Characteristics As McGoon has noted, the natural phenomena is considered ideal from a hemodynamic standpoint. The biologic valves enjoy a great advantage as they allow central flow and natural semilunar cusp motion. Thus, aortic homografts and autologous pulmonary valves have an advantage over the heterograft and fascia lata valves. Ball and disc valves, although they have functioned adequately with relatively low hemolysis and transvalvular gradients, cause more turbulence from having the poppet directly in the path of blood flow. The tilting disc valve is an attempt to rectify this problem, but Kay and his co-workers 13~ have shown that the homograft valve has better hemodynamic characteristics when it is of proper size and functioning without leak.

Thrornboembolism Even though the newer cloth-covered valves have demonstrated a marked decrease in thromboembolic complications, there is general unanimity of opinion that the biologic valves hold a distinct advantage. Patients with these new valves still require anticoagulant therapy, and such therapy has been the cause of an added morbidity and mortality.

Patient Morbidity and Mortality As we have indicated, these are the most difficult factors to compare as there is a paucity of good, accurate actuarial survival data. It is clear that tissue valves damaged by chemical or physical trauma do not hold up well. This results in a definite decrease in valve survival, which is reflected by some decrease in patient survival. In general, however, tissue valve failure should result in reoperation and not in death. A comparison of Starr-Edwards vs. homograft results at Birmingham and Stanford shows no significant advantage of prosthetics over homografts 43,44 (Fig. 10). This is supported by the comparison of actuarial data between centers. Patient safety is of such primary concern as to be the single most crucial criteria for valve selection. Criteria such as availability, size choice, and ease of insertion should be of far less concern than the hemodynamic characteristics, long-term function, and risks from sudden catastrophic events. Tissue valves admittedly have a record fraught with problems of valvular regurgitation resulting from a multitude of causes. This has rarely resulted in death and stroke with significant residuum. Prosthetics, on the other hand, have traditionally been associated with sudden, catastrophic complications. SUMMARY

We have surveyed the medical literature for reports of cardiac valve replacement. While the objectives of these reports are often diverse, they usually refer to the functional adequacy of the valve in question. Frequently the objective is to compare the function in two or more valve types. A variety of statistics can be derived from these patient data. Patient survival is the most consistently reported figure and is undoubtedly the most important and most accurate factor to consider. While actuarial curves are a well-described

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method of reporting these survival figures, there are still many centers that report flat percentage figures that do not consider the crucial period of postoperative follow-up. In addition to these actuarial survival curves, some attempt should be made to indicate which deaths are related to cardiac valve replacement and which are clearly unrelated. While there always must be some bias in this selection, it is probably most accurate to include in the valve-related category all sudden deaths, unknown and questionable deaths, and all patients lost to follow-up. This will clearly define those patients who have succumbed to causes completely unrelated to the valve. These valve-related figures obviously should also be reported on an actuarial basis. Along with an analysis of survival, the incidence of complications must be considered in evaluating the clinical results. While these data are often far less accurate than the survival data, they can reflect the general comparative trends in different valve types. For example, while definite thromboembolic episodes are usually reported, suspicious, unknown, or sudden episodes are rarely included. The incidence of hemorrhage from Coumadin is almost never indicated. It is clear from the assessment of these series that the complication rate must also be expressed on an actuarial basis as a percentage of those patients who are alive and well in a given follow-up interval. The combined incidence of deaths and complications will provide the most accurate impression of how well a particular valve can function. Figure 9 presents our total homograft experience as an example of actuarially reported survival, valve-related deaths, and valve-related complications. In statistical reporting of human cardiac valve data, the postoperative interval of follow-up is critical. With the types of valves presently being used, intervals shorter than 18-36 mo do not provide us with a significant follow-up period. Not until follow-up data reaches the 5-10-yr mark does it become meaningful to the assessment of long-term valve function. In reviewing the literature, no group with a 5-10-yr follow-up reports greater than 50% of the original patients to be alive and well without having suffered any significant complication since surgery. This applies to all types of valve replacement. This low incidence of perfect results is counterbalanced by the fact that deaths attributed directly to the valve are consistently less than 10%. This does not mean that in further follow-up many of these problems and complications are not going to result in a more significant mortality rate. It is also repeatedly stated that the recent advances and alterations in valve design will significantly influence the long-range outlook of valve replacement. It must be carefully indicated that this is speculation and is not supported by factual data. Attempting to draw finite conclusions from data comparing valve types is difficult. Two or three impressions stand out. It would appear, for example, that the fresh aortic homograft has a significantly better long-term record than other types of tissue valves. Both the frozen-irradiated homograft and the gluteraldehyde heterograft are reporting excellent early results. Of the prosthetics, the Smelloff-Cutter valve has probably the best long-term results, and, as opposed to most, it has not undergone recent design change. Cloth-covered valves have had a definite impact on the incidence of thromboembolism and can be used without the

PRESENT STATUS OF HOMOGRAFT VALVES

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o n g o i n g risk o f a n t i c o a g u l a n t s . W e a r e i m p r e s s e d by o u r o b s e r v a t i o n t h a t t h e e a r l i e r S t a r r - E d w a r d s v a l v e i n v a r i a b l y h a d a t t a c h e d fibrin and t h r o m b u s deposits, e v e n s e v e r a l y r a f t e r i m p l a n t a t i o n . C l o t h - c o v e r e d v a l v e s a r e f r e e o f t h e s e p e r s i s t e n t t h r o m b i and s i g n i f i c a n t l y d e c r e a s e t h e o n g o i n g p a t i e n t risk f r o m e m b o l i s m . U n f o r t u n a t e l y , t h e e f f e c t s o f this d e s i g n c h a n g e m a y n o t be e n t i r e l y beneficial. In all five o f the c l o t h - c o v e r e d v a l v e s we h a v e i n s p e c t e d at reop e r a t i o n , t h e r e has b e e n d e f i n i t e f a b r i c d e t e r i o r a t i o n a n d in o n e i n s t a n c e t h e c l o t h dehisced completely from the cage. It is not p o s s i b l e for us, t o d a y , to s t a t e w h i c h v a l v e t y p e is best. T h e r e s u l t s o f v a l v e r e p l a c e m e n t with s h o r t - t e r m f o l l o w - u p has c e r t a i n l y i m p r o v e d m a r k e d l y o v e r t h e 10-12 y r o f use. S t a t i s t i c s , h o w e v e r , do n o t y e t i n d i c a t e any s i g n i f i c a n t i m p r o v e m e n t in l a t e f o l l o w - u p d a t a . REFERENCES

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PRESENT STATUS OF HOMOGRAFT VALVES

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PRESENT STATUS OF HOMOGRAFT VALVES

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