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Considerations in the development of artificial heart valve substitutes for use in infants and small children
Considerations in the development of artificial heart valve substitutes for use in infants and small children Experimental studies carried out in our laboratory suggest that it is possible to develop a family of stem-supported tissue valve substitutes suitable for use in tissue annuli of the hearts of small children in tissue annulus sizes ranging from 12 to 22 mm. Either glutaraldehyde-preserved, stent-supported primate tissue aortic valves or tissue leaflet valves constructed from dura mater preserved in 98 per cent glycerine can be used. In both instances, hemodynamic assessment of the valve substitutes in a mock circulation indicated that function was acceptable at the cardiac outputs normal for infants and children during the first few years of life. Stent-supported dura mater valves 16 mm. in diameter have been used to replace the mitral valve in 2 infants 7 and 8 months of age with complete atrioventricular canal defects and mitral regurgitation, one of whom survives with demonstratable satisfactory hemodynamic function of the valve substitute.
Nina S. Braunwald, M.D., F.A.C.S., Maurice Brais, M.D., and Aldo Castaneda, M.D., F.A.C.S., Boston, Mass.
/artificial heart valves of various designs, suitable for use in adult patients, have been available for over a decade and their use has been demonstrated to extend the life span of patients requiring valve replacement and to afford considerable symptomatic improvement. In the case of the infant or child requiring valve replacement, the selection of the valve substitute provides no special problem if the tissue annulus happens to be large enough to accomodate an adultsized artificial heart valve. This is not uncommonly encountered as a result of secondary enlargement of the heart and annulus owing to the underlying disease process. It is apparent that when an adult-sized valve is utilized, hemodynamic performance and clinical benefit are comparable to that found in an adult population requiring valve replacement. However, with a reduced annulus size, particularly the very small annuli present in the first few years of life, it becomes necessary to define the hemodynamic requirements of the patient more particularly as well as to make some predictions as to the rate of growth for a given child From the Children's Hospital Medical Center, Boston, Mass. 02115. This study was supported by Grant No. 1 ROI HL15631 from the National Heart and Lung Institute, U.S. Public Health Service. Received for publication Feb. 17, 1976. Accepted for publication July 23, 1976.
before selecting the valve substitute which will assure an acceptable period of functional improvement. For most types of artificial heart valves presently available, the smaller the tissue annulus, the more limited the hydraulic function. During the first few years of life the problem is particularly accentuated and the artificial valves presently available for clinical use are either too large or too bulky to provide an adequate substitute. As a result, it is not unusual for the cardiologist caring for infants and very young children with serious valve malfunction to manage these patients conservatively for as long as possible. In some instances this results in irreversible impairment of myocardial function or even death before the patient is referred to the cardiovascular surgeon. Thus the need for further efforts directed toward the development of improved heart valves for use in young children is clear. Investigations in our laboratory directed toward the development of hemodynamically acceptable valve substitutes suitable for use in hearts with small annulus dimensions form the subject of this report. Materials and methods Two approaches were explored in this study for the fabrication of the small valves. The first used glutaraldehyde-preserved aortic valves obtained from 539
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hearts. Data were obtained correlating the annulus size with the age as well as the weight of the patient in order to develop a source of valves of appropriate size for a valve bank. Measurements were made on normal hearts obtained from infants and children at this institution dying of noncardiac causes. Method
Fig. 1. Appearance of a trimmed human aortic valve obtained from a 10-month-old infant donor. The valve is fixed in glutaraldehyde and mounted on a modified Hancock stent (tissue annulus 15 mm.). The sewing ring is unpadded. primate donors (both human and monkey) and mounted on miniaturized polypropylene stents* (Fig. 1). In the other, valves fashioned from human dura mater preserved in 98 per cent glycerine and mounted on fabric-covered titanium supports according to the technique of Puig, Zerbini, and their associates 1, 2 were employed. In both instances, because the fabric covering used on the stent as well as the sewing ring had to be reduced to the smallest possible dimensions to allow for optimum hydraulic performance for a given sized annulus, emphasis was placed on maintaining the largest possible ratio of orifice diameter to total prosthetic valve size in the construction of each type of substitute. As a first step, a donor source of small size aortic valves had to be developed. Stent-supported aortic valves obtained from primate donors. Monkeys. Measurements of the diameter of the aortic valve annulus were made in a series of fresh heart specimens obtained from rhesus (Macaca mulatto) and stumptail (Macaca arctiodes) monkeys of various weights in order to develop a source of donor aortic valves in small sizes for mounting on stent supports. A specially designed valve sizor graduated in millimeters was employed to measure the diameter of the valve annuli. Human donors. As an alternate source of donor material, similar data were obtained from human This portion of the work was carried out in collaboration with Hancock Laboratories, Inc., Anaheim, Calif.
After measurements were completed, the aortic root was removed intact from the donor heart, including the aortic valve and a portion of the ascending aorta and aortic leaflet of the mitral valve, and fixed under 100 mm. Hg pressure in stabilized glutaraldehyde* for 12 hours. The specimens were then trimmed, mounted on Dacron fabric-covered stent supports under sterile conditions, and returned to sterile jars containing the glutaraldehyde fixative. A portion of the trimmed aortic wall was sent to bacteriology for culture and only valves having negative cultures were used. The sewing rings, 3 to 5 mm. in width, used in the construction of the valves were purposely not padded to assure compressibility in a small heart and at the same time allow for the insertion of the largest possible stent size for a given tissue annulus. Both metal and polypropylene stent supports 1 mm. in thickness were used to mount the valves. The former could be more easily machined in very small sizes whereas the latter had the advantage of flexibility, thought to be important in reducing strain on mounted valve leaflets. The metal stents made of titanium were obtained with internal diameters graded in 2 mm. increments from 10 to 22 m m . t The flexible polypropylene stents were specially fabricated by the Hancock Laboratories and had internal diameters of 13 and 15 mm. before being covered with fabric. Valve substitutes fabricated from human dura mater. Human (cranial) dura mater collected from patients between the ages of 15 and 55 years coming to autopsy was procured, washed, and placed in 98 per cent glycerine for a 2 week period of time. It was then cut to size and mounted on fabric-covered titanium stent supports according to the technique described by Ionescu 3 - 5 and modified by Zerbini. Templates were used to cut the dura mater to size and mandrils to shape the aortic cusps. Testing of mounted valves in a mock circulation Testing of the hydraulic capabilities of the valves mounted on stents was carried out in a mock circulatory system to permit assessment of the gradients developed *Hancock Laboratories, Inc., Anaheim, Calif. tBio-Med Engineering, Ltd., Yorkshire, England.
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Table I. Correlation between the weight of monkey donors and the diameter of the aortic valve annulus* Species t Rhesus Rhesus Rhesus Stumptail Stumptail Rhesus Rhesus Rhesus
Weight (Kg.) 3.7 6.2 7.9 7.5 7.8 8.8 8.9 10.0
ID of aortic valve annulus (mm.) 7.5 8.5 8.5 7.5 10.0 10.0 11.0 12.0
Legend: ID, Inner diameter. *Fresh autopsy specimens. tRhesus is Macaca mulatta. Stumptail is Macaca arctoides.
across the valves at progressively increasing blood flows from zero to 10 L. per minute. The valves mounted on fabric-covered stents were placed in a Plexiglas chamber and strain gauges were connected to stopcocks positioned proximal and distal to the valve in the chamber and attached to a Hewlett-Packard PolyViso recorder. The system was filled with a blood analogue fluid consisting of 36.7 per cent glycerine solution in water. Flows across the valve were progressively increased at graded intervals by means of a Sams roller pump and the pressure difference recorded on paper with a direct ink stylus. Results Aortic valves obtained from subhuman primate donors. The correlation between aortic annulus size, species, and weight of the animal is shown in Table I. The aortic annulus size was found to be more dependent upon the weight of the donor animal than on the species. Aortic valves obtained from human autopsy donors. Correlation between the aortic annulus size, weight, and age of the patient from whom the fresh human hearts were obtained is shown in Table II, and correlation between age and aortic and mitral annulus size in normal human hearts fixed in formalin is shown in Table III. Examination of the aortic valve specimens obtained from primate donors, both human and subhuman, revealed anatomic features which made them more favorable for the construction of small size valve substitutes than is the case with grafts obtained from alternate donor sources, such as pigs and calves, which were examined in preliminary studies. The ridge of cardiac muscles so prominent beneath the right coronary cusp in the pig and calf hearts was noted to be virtually nonexistent in the trimmed aortic valves
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Table II. Correlation between patient's age and the aortic annulus size in normal hearts of infants and children* Age
Weight
1 day 7 days 10 days 1 'A mo. 2'/2 mo. 10 mo. 11 mo. lyr. 2yr. 3yr. 3 7 / 1 2 yr. 38/i2 yr. 3"/i2 yr. 4 6 /i2 yr. 5yr. 5u/i2yr. 76/i2 yr. 8 yr. 8V12 yr. 9"/i2 yr. 12 yr. 15 yr.
(lbs.)
8.0 7.0 8.0 9.5 8.6 16.0 19.8 23.0 24.0 29.5 46.0 20.0 37.5 41.8 52.0 37.5 44.0 56.0 66.0 59.0 43.0 84.0
ID of aortic valve annulus (mm.) 6.0 6.0 6.0 6.5 10.0 10.0 12.0 10.0 13.0 13.0 12.0 12.0 12.0 14.0 14.0 13.0 12.0 13.0 15.0 16.0 15.0 18.0
*Fresh autopsy specimens.
Table III. Diameter of aortic and mitral valve annulus in normal infants and children up to the age of 6 years * Age
Aortic (mm.)
Mitral (mm.)
0-1 wk. 1 wk.-6 mo. 6 mo.-l yr. 1-2 yr. 2-3 yr. 3-6 yr.
5-9 6-10 7-11 10-12 10-13 13-15
7-12 7-15 9-16 13-20 14-18 18-20
*Formaldehyde-fixed autopsy specimens.
obtained from both human and monkey donors (Fig. 2). Asa result the right coronary leaflet tended to fold back more completely against the aortic wall and was less obstructive to blood flow when mounted on a stent of small diameter. Assessment in a mock circulation The gradients developed across a series of primate aortic valves mounted on fabric-covered stent supports at varying flows in the in vitro duplicator system are shown in Fig. 3. The internal diameter represents the diameter of the mounted aortic valve whereas the external diameter represents the outside diameter of the
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l/min
Fig. 3. Gradients developed across primate aortic valves (rhesus and stumptail monkeys) mounted on fabric-covered stents at increasing flows in a mock circulation. ID, Internal diameter of mounted valve. OD, Outside diameter including 3 mm. sewing ring (tissue annulus).
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Fig. 2. A, Appearance of a trimmed aortic valve obtained from a rhesus monkey. The internal diameter is 10 mm. B, The absence of a shelf of muscle tissue beneath the right coronary cusp is evident. completed prosthesis and includes a 3 mm. Dacron fabric sewing ring. The data indicate that the gradients which are developed are within an acceptable range at flow rates up to 3 L. per minute which occur in children during the first 5 to 7 years of life, as reported in the literature 6 " 8 (Fig. 4). The results of the flow studies carried out on dura mater valves mounted on fabric-covered stents are shown in Fig. 5. The internal diameter of the mounted completed tissue valve is virtually the same as that of the fabric-covered stent and represents the effective
6 7 8 9 » AGE (yeare)
II 12 13 14 15
Fig. 4. Cardiac output compared with age for normal children from birth to maturity (15 years). It can be seen that the normal cardiac output is less than 3 L. per minute during the first 5 to 7 years of life. orifice diameter of the valve. As can be seen, the flow characteristics of these valves are somewhat more favorable for a given size stent than is the case for primate aortic valves mounted on a stent of equivalent size, because of the absence of the aortic wall and annulus tissue which occupies space within the stent when an allograft or xenograft is mounted on a support (Fig. 6). Clinical experience Dura mater valves mounted on stents having a tissue annulus of 16 mm. were used to replace the mitral valve in 2 infants less than one year of age with
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mmHg
Fig. 5. Gradients developed across human dura mater valves mounted on fabric-covered stents at increasing flows in sizes I4 through 22 mm. Sizes reflect outside diameter of fabric-covered stent (tissue annulus). complete atrioventricular canal defects and mitral regurgitation. In both instances, satisfactory hemodynamic performance of the valve substitute has been demonstrated in the early postoperative period. Case reports CASE 1. K. T. (No. 83-91-67), a 7-month-old, 4.8 kilogram female infant with trisomy 21 and congestive heart failure since birth, underwent cardiac catheterization studies because of continued clinical deterioration. A complete atrioventricular canal defect with mitral regurgitation was demonstrated, together with a patent ductus arteriosus and pulmonary hypertension with equal pressures in the systemic and pulmonary arteries. The Qp/Qs ratio was 2.6. The patient was taken to the operating room on Jan. 27, 1976. With the infant under deep hypothermia, the ductus arteriosus was ligated and complete repair of the endocardial cushion defect was carried out with a Teflon fabric patch. The cleft mitral valve, deficient in leaflet tissue, was replaced with a 16 mm. dura mater valve. Following rewarming to normothermic levels the infant came off cardiopulmonary bypass without any difficulty. Simultaneous left atrial and left ventricular pressure measurements revealed a mean gradient across the dura mater valve of 2 to 3 mm. Hg and an end-diastolic gradient of zero. The left atrial pressure was 15 mm. Hg. The cardiac index was 1.7 L. per minute per square meter. One day following operation, the infant was doing well and was fully saturated with a central venous pressure of 10 mm. Hg, a left atrial pressure of 15, a pulmonary artery pressure of 30/27, and a systemic arterial pressure of 95/54 mm. Hg. There was no evidence of a residual intracardiac shunt. On the second day postoperatively, following extubation, the baby developed a mucus plug and sustained a respiratory arrest. Although resuscitated and hemodynamically stable following reintubation, she died from the neurologic and pulmonary consequences of this episode several days later. At autopsy the intracardiac repair was complete, the dura mater valve was clean and well placed, but severe bronchopneumonic changes were present in both lungs. CASE 2. A. H. (No. 85-18-06), an 8-month-old male infant weighing 6.8 kilograms, was admitted to the hospital. History and physical findings were consistent with the diag-
mmHg 16
# ODmm » Tissue annulus
Fig. 6. Comparison of gradients developed across human aortic valve and dura mater leaflet valve mounted on fabriccovered stent of comparable size at increasing flows. It is evident that, at comparable flows, the gradient is less for the dura mater valve. This reflects an increased effective orifice size for a given tissue annulus size when using a dura mater valve. nosis of pneumonia and congestive heart failure in the presence of an atrioventricular canal defect. Following appropriate medical therapy with antibiotics, digitalis, and diuretics, cardiac catheterization was carried out confirming the presence of a complete atrioventricular canal, pulmonary artery pressure at systemic levels, severe mitral regurgitation, and a left ventricular end-diastolic pressure of 15 mm. Hg. The Qp/Qs ratio was 2.6. The chest x-ray film revealed marked cardiomegaly (Fig. 7, A). On Jan. 29, 1976, he was taken to the operating room. With the infant under deep hypothermia, a complete atrioventricular canal defect with common atrium was repaired and the cleft mitral valve replaced with a 16 mm. dura mater valve. In the region of the ventricular crest the sewing ring of the valve was secured to the Teflon fabric patch which was tailored to reconstruct the ventricular and atrial septum. The patient was rewarmed to normothermic levels and came off
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Fig. 7. Chest x-ray films of an 8-month-old infant with complete atrioventricular canal defect and severe mitral regurgitation (A) preoperatively and (B) following insertion of a 16 mm. dura mater mitral prosthesis. bypass without any difficulty. Atrioventricular dissociation was present necessitating the use of a pacemaker. The mean left atrial—left ventricular pressure gradient across the valve was 4 to 5 mm. Hg at a heart rate of 110 beats per minute. On thefirstpostoperative day, the cardiac index was 4.6 L. per minute per square meter. He was extubated without difficulty and had no evidence of a residual shunt. The 16 mm. dura mater valve appeared to be functioning satisfactorily, and the infant has shown progressive clinical improvement postoperatively (Fig. 7, B). Discussion As the capabilities for operating on neonates, infants, and small children with severe forms of congeni-
The Journal of Thoracic and Cardiovascular Surgery
tal heart disease continue to be refined further, the need for improved heart valve substitutes for use in this type of patient population becomes more pressing. Included in this group are infants born with congenital aortic stenosis, mitral stenosis associated with parachute mitral valve, endocardial cushion defects, truncus arteriosus, and other anomalies. Although a considerable clinical experience with older children requiring heart valve replacement has been accumulated to date, valve replacement in the infant and young child remains more limited.9-12 It is likely that, if an improved family of valve substitutes were available for use in small hearts with a diminutive annulus, many more infants with congenital valvular lesions such as truncal valve insufficiency or mitral valve insufficiency associated with endocardial cushion defects could be referred for surgical therapy. Although in the latter instance valvuloplasties sometimes render the valve competent, this is not always possible. Even if acceptable valve substitutes in smaller sizes become available for this very young population, valve replacement would have to be considered a palliative procedure. In most instances it is likely that the valve will be outgrown and have to be replaced at least once before the patient reaches maturity. On the other hand, a significant number of adult patients in whom earlier vintages of prosthetic heart valves had been implanted have now undergone repeat valve replacement without undue difficulty and at an acceptable operative mortality rate, so that this concept seems more readily acceptable at the present time than it was several years ago. Of course, the younger the child is at the time of initial valve replacement, the more likely it is that at least one additional valve replacement operation will have to be carried out before adulthood, both by virtue of growth and by virtue of durability problems. Although concern has been expressed about the lack of growth of the annulus if a prosthesis of fixed ring size is inserted early in life, studies in our laboratory in the past suggest that this may not necessarily be a problem. Prosthetic ball-valve prostheses inserted in 6-week-old calves weighing 140 pounds at the time of initial operation were examined 1 to 3 years postoperatively at the time of full growth and when the animals' weight had increased to over 1,000 pounds. The hearts and periannular tissue had dilated sufficiently so that it would have been possible to insert a larger prosthesis at this time had this been necessary.13 Furthermore, techniques for enlarging the aortic annulus have recently been described and are being used clinically with success.14, 15 It is appreciated that the use of fresh donor tissue has
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certain advantages from the point of view of cell viability and possibly the durability of the leaflet substance. However, the practical problems of maintaining a storage bank of valve substitutes for use in children dictates that it is essential to employ a technique which allows for storage of the material for considerable periods of time. While the number of children requiring heart valve replacement is increasing as our techniques of diagnosis and surgical therapy improve, the incidence of very young children requiring valve substitution in any one institution remains relatively small over a given period of time. Thus the techniques of preservation explored in this study were those which allowed for reasonable storage periods for the completed valves. The techniques of preservation selected were those which have already been shown in clinical practice to be associated with acceptable periods of durability of up to 5 years.2, 16 Analysis of the tissue annulus size of several models of prosthetic heart valves currently available suggests that for the most part they are too large to use in many infants and children requiring heart valve replacement during the first few years of life. Bioengineers have indicated that it is not practical or feasible to decrease the size of the valves of the conventional design any further, using techniques currently available, without compromising hydraulic function to an unacceptable extent. In order to design heart valve substitutes of the order of magnitude which would be appropriate for the annulus size of the very small child, it was felt desirable to use tissue valves of central flow design known to be relatively nonthrombogenic and at the same time having a low profile suitable for use in a small cardiac chamber. Additionally, a valve substitute with flexible tissue leaflets would be expected to open and close more efficiently at the more rapid rates which are normal in infancy and early childhood than would a prosthetic valve relying on the motion of a central ball occluder or tilting disc to effect full opening and closing. The sewing ring of an artificial valve serves a dual purpose: Not only is it used to fix the valve to the annulus but, because of its padding effect, it also decreases the likelihood of a perivalvular leak. However, in the case of children with very small tissue annuli, the hemodynamic price paid for the presence of a generous buffer zone increases significantly as the annulus size decreases. The greater the space used up for frame, stent, and tissue, the less the space left for an effective orifice through which blood can flow. In many adults requiring prosthetic heart valve replacement, there is considerable annular calcification sec-
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ondary to atherosclerotic or rheumatic heart disease, and the need for a generous cushion seal provided by the sewing ring becomes quite important in securing the valve to the heart. On the other hand, most young children requiring heart valve replacement tend to have annuli which are quite pliable. This negates many of the benefits anticipated from the use of the oversized sewing ring present on many commercially available valves at the present time. The results of the studies carried out in a mock circulation employing tissue valves of small diameter mounted on fabric-covered stent supports revealed that it is possible to develop a valve substitute with a sewing ring in the 12 to 20 mm. size range which allows for adequate blood flow without the development of a significant gradient for flow requirements normal during the first few years of life. Since, in vivo, the diastolic filling period and systolic ejection periods occupy only a portion of each cycle, the instantaneous flow is higher than minute flow. However, in infants and children the relationship between cardiac output and body surface area is such that the gradients will still fall in the acceptable range when the small-sized valves are used. Thus acceptable hemodynamic palliation can be anticipated at least for several years in the very young patient following the insertion of such a valve. The hemodynamic studies described in this report tend to support the impression that there is an advantage to constructing the leaflet portion of the valve of tissue such as dura mater instead of using an allograft or xenograft aortic valve. However carefully the aortic valves are trimmed, the space consumed by the interposition of the residual aortic wall and annulus within the stent support limits the effective orifice remaining for the egress of blood. When sheets of dura mater are used to construct the valve, the diameter of the effective orifice approaches that of the fabric-covered stent support, eliminating this factor. In valves having a tissue annulus diameter greater than 24 mm. this is probably less of a practical consideration. Above this size, xenografts mounted on stent supports have been shown to function quite satisfactorily at the cardiac outputs predicted for most patients requiring heart valve substitution.17' 18 However, below 24 mm., and especially in the tissue annulus size range anticipated in many infants and young children requiring valve substitution (i.e., 12 to 18 mm.), this factor became more progressively significant if unacceptable stenosis is to be avoided postoperatively.19 On the other hand, it becomes technically more difficult to fashion competent trileaflet valves from sheets of tissue in sizes less than 14 mm.
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Initially, a number of species of animals were explored as potential donors for construction of the small sizes of valves. Ultimately, the primates were selected to serve as donors. It was found that in the size range required for this study the aortic wall tended to be thinner than that found in dogs, sheep, pigs, or calves. At the same time, the muscular ridge present beneath the right coronary cusp was less pronounced in primates and so allowed for improved flexibility of the leaflet occupying this third of the valve circumference. An additional advantage associated with the use of a tissue valve relates to its low incidence of thromboembolic complications in patients not receiving anticoagulants. While review of the literature to date indicates that complications, particularly hemorrhagic, do occur because of the increased physical activity of most children and the associated increased risk of trauma, the desirability of developing a heart valve substitute which does not require permanent anticoagulation becomes more attractive in the very young. It was for this reason, together with the bioengineering limitations already mentioned relating to the development of improved rigid valve designs in the very small size, that the thrust of the present developmental effort in this institution was directed toward finding improved tissue valve substitutes in the very small dimensions required. REFERENCES 1 Puig, L. B., Verginelli, G., Belotti, G., Kawabe, L., Frack, C. C. R., Pileggi, F., Decourt, L. V., and Zerbini, E. J.: Homologous Dura Mater Cardiac Valve, J. THORAC. CARDIOVASC. SURG. 64: 154,
1972.
2 Puig, L. B., Verginelli, G., Iryia, K., Kawabe, L., Bellotti, G., Sosa, E., Pileggi, F., and Zerbini, E. J.: Homologous Dura Mater Cardiac Valves, J. THORAC. CARDIOVASC. SURG. 69: 722,
1975.
3 Ionescu, M. I., and Ross, D. N.: Heart Valve Replacement With Autologous Fascia Lata, Lancet 1: 335, 1969. 4 Ionescu, M. I., Ross, D. N., Deac, R. C , Wooler, G. H.: Heart Valve Replacement With Autologous Fascia Lata, J. THORAC. CARDIOVASC. SURG. 60: 331,
1970.
5 Bartek, I. T., Holden, M. P., and Ionescu, M. I.: Frame-Mounted Tissue Heart Valves: Technique of Construction, Thorax 29: 51, 1974.
6 Jacob, W.: The Relation Between Cardiac Output and Body Size, Br. Heart J. 25: 425, 1963. 7 Jegier, W., Sekely, P., Auld, A. M., Simpson, R., and McGregor, M.: The Relation Between Cardiac Output and Body Size, Br. Heart J. 25: 425, 1963. 8 Rudolph, A.: Congenital Diseases of the Heart, Chicago, 111., Year Book Medical Publishers, Inc. 9 Robinson, G., and Young, D.: Secondary Implantation of a Mitral Valve Prosthesis in a Child, Ann. Thorac. Surg. 2: 208, 1966. 10 Young, D., and Robinson, G.: Successful Valve Replacement in an Infant With Congenital Mitral Stenosis, N. Engl. J. Med. 270: 660, 1964. 11 Castaneda, A. R., Nicoloff, D. M., Moller, J. H., and Lucas, R. V.: Surgical Correction of Complete Atrioventricular Canal Utilizing Ball Valve Replacement of the Mitral Valve, J. THORAC. CARDIOVASC. SURG. 62: 926,
1971. 12 Blieden, L. C , Castaneda, A. R., Nicoloff, D. M., Lillehei, C. W., and Moller, J. H.: Prosthetic Valve Replacement in Children: Results in 44 Patients, Ann. Thorac. Surg. 14: 545, 1972. 13 Detmer, D. E., and Braunwald, N. S.: Long-Term Fate of Autogenous Tissue Coverings on Prosthetic Heart Valves, Ann. Surg. 173: 139, 1971. 14 Konno, S., Imai, Y., Iida, Y., Nakajima, M., and Tatsuno, K.: A New Method for Prosthetic Valve Replacement in Congenital Aortic Stenosis Associated With Hypoplasia of the Aortic Valve Ring, J. THORAC CARDIOVASC SURG. 70: 909,
1975.
15 Wittig, J., McConnell, D., Buckberg, G., and Mulder, D.: Aortic Valve Replacement in the Young Child, Ann. Thorac. Surg. 19: 40, 1975. 16 Zuhdi, N., Hawley, W., Voehl, V., Hancock, W., Carey, J., and Greer, A.: Porcine Aortic Valves as Replacements for Human Heart Valves, Ann. Thorac. Surg. 17: 479, 1974. 17 Horowitz, M. S., Goodman, D. J., Fogarty, T. J., and Harrison, D. C : Mitral Valve Replacement With the Glutaraldehyde-Preserved Porcine Heterograft, J. THORAC CARDIOVASC. SURG. 67: 885,
1974.
18 Mclntosh, C. L., Michaelis, L. L., Morrow, A. G., Itscoitz, S. B., Redwood, D. R., and Epstein, S. E.: Atrioventricular Valve Replacement With the Hancock Porcine Xenograft: A Five-Year Clinical Experience, Surgery 78: 768, 1975. 19 Schultz, D. M., and Giordano, D. A.: Hearts of Infants and Children, Arch. Pathol. 74: 78, 1962.
Nina S. Braunwald, M.D., F.A.C.S., Maurice Brais, M.D., and Aldo Castaneda, M.D., F.A.C.S., Boston, Mass.
/artificial heart valves of various designs, suitable for use in adult patients, have been available for over a decade and their use has been demonstrated to extend the life span of patients requiring valve replacement and to afford considerable symptomatic improvement. In the case of the infant or child requiring valve replacement, the selection of the valve substitute provides no special problem if the tissue annulus happens to be large enough to accomodate an adultsized artificial heart valve. This is not uncommonly encountered as a result of secondary enlargement of the heart and annulus owing to the underlying disease process. It is apparent that when an adult-sized valve is utilized, hemodynamic performance and clinical benefit are comparable to that found in an adult population requiring valve replacement. However, with a reduced annulus size, particularly the very small annuli present in the first few years of life, it becomes necessary to define the hemodynamic requirements of the patient more particularly as well as to make some predictions as to the rate of growth for a given child From the Children's Hospital Medical Center, Boston, Mass. 02115. This study was supported by Grant No. 1 ROI HL15631 from the National Heart and Lung Institute, U.S. Public Health Service. Received for publication Feb. 17, 1976. Accepted for publication July 23, 1976.
before selecting the valve substitute which will assure an acceptable period of functional improvement. For most types of artificial heart valves presently available, the smaller the tissue annulus, the more limited the hydraulic function. During the first few years of life the problem is particularly accentuated and the artificial valves presently available for clinical use are either too large or too bulky to provide an adequate substitute. As a result, it is not unusual for the cardiologist caring for infants and very young children with serious valve malfunction to manage these patients conservatively for as long as possible. In some instances this results in irreversible impairment of myocardial function or even death before the patient is referred to the cardiovascular surgeon. Thus the need for further efforts directed toward the development of improved heart valves for use in young children is clear. Investigations in our laboratory directed toward the development of hemodynamically acceptable valve substitutes suitable for use in hearts with small annulus dimensions form the subject of this report. Materials and methods Two approaches were explored in this study for the fabrication of the small valves. The first used glutaraldehyde-preserved aortic valves obtained from 539
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hearts. Data were obtained correlating the annulus size with the age as well as the weight of the patient in order to develop a source of valves of appropriate size for a valve bank. Measurements were made on normal hearts obtained from infants and children at this institution dying of noncardiac causes. Method
Fig. 1. Appearance of a trimmed human aortic valve obtained from a 10-month-old infant donor. The valve is fixed in glutaraldehyde and mounted on a modified Hancock stent (tissue annulus 15 mm.). The sewing ring is unpadded. primate donors (both human and monkey) and mounted on miniaturized polypropylene stents* (Fig. 1). In the other, valves fashioned from human dura mater preserved in 98 per cent glycerine and mounted on fabric-covered titanium supports according to the technique of Puig, Zerbini, and their associates 1, 2 were employed. In both instances, because the fabric covering used on the stent as well as the sewing ring had to be reduced to the smallest possible dimensions to allow for optimum hydraulic performance for a given sized annulus, emphasis was placed on maintaining the largest possible ratio of orifice diameter to total prosthetic valve size in the construction of each type of substitute. As a first step, a donor source of small size aortic valves had to be developed. Stent-supported aortic valves obtained from primate donors. Monkeys. Measurements of the diameter of the aortic valve annulus were made in a series of fresh heart specimens obtained from rhesus (Macaca mulatto) and stumptail (Macaca arctiodes) monkeys of various weights in order to develop a source of donor aortic valves in small sizes for mounting on stent supports. A specially designed valve sizor graduated in millimeters was employed to measure the diameter of the valve annuli. Human donors. As an alternate source of donor material, similar data were obtained from human This portion of the work was carried out in collaboration with Hancock Laboratories, Inc., Anaheim, Calif.
After measurements were completed, the aortic root was removed intact from the donor heart, including the aortic valve and a portion of the ascending aorta and aortic leaflet of the mitral valve, and fixed under 100 mm. Hg pressure in stabilized glutaraldehyde* for 12 hours. The specimens were then trimmed, mounted on Dacron fabric-covered stent supports under sterile conditions, and returned to sterile jars containing the glutaraldehyde fixative. A portion of the trimmed aortic wall was sent to bacteriology for culture and only valves having negative cultures were used. The sewing rings, 3 to 5 mm. in width, used in the construction of the valves were purposely not padded to assure compressibility in a small heart and at the same time allow for the insertion of the largest possible stent size for a given tissue annulus. Both metal and polypropylene stent supports 1 mm. in thickness were used to mount the valves. The former could be more easily machined in very small sizes whereas the latter had the advantage of flexibility, thought to be important in reducing strain on mounted valve leaflets. The metal stents made of titanium were obtained with internal diameters graded in 2 mm. increments from 10 to 22 m m . t The flexible polypropylene stents were specially fabricated by the Hancock Laboratories and had internal diameters of 13 and 15 mm. before being covered with fabric. Valve substitutes fabricated from human dura mater. Human (cranial) dura mater collected from patients between the ages of 15 and 55 years coming to autopsy was procured, washed, and placed in 98 per cent glycerine for a 2 week period of time. It was then cut to size and mounted on fabric-covered titanium stent supports according to the technique described by Ionescu 3 - 5 and modified by Zerbini. Templates were used to cut the dura mater to size and mandrils to shape the aortic cusps. Testing of mounted valves in a mock circulation Testing of the hydraulic capabilities of the valves mounted on stents was carried out in a mock circulatory system to permit assessment of the gradients developed *Hancock Laboratories, Inc., Anaheim, Calif. tBio-Med Engineering, Ltd., Yorkshire, England.
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Table I. Correlation between the weight of monkey donors and the diameter of the aortic valve annulus* Species t Rhesus Rhesus Rhesus Stumptail Stumptail Rhesus Rhesus Rhesus
Weight (Kg.) 3.7 6.2 7.9 7.5 7.8 8.8 8.9 10.0
ID of aortic valve annulus (mm.) 7.5 8.5 8.5 7.5 10.0 10.0 11.0 12.0
Legend: ID, Inner diameter. *Fresh autopsy specimens. tRhesus is Macaca mulatta. Stumptail is Macaca arctoides.
across the valves at progressively increasing blood flows from zero to 10 L. per minute. The valves mounted on fabric-covered stents were placed in a Plexiglas chamber and strain gauges were connected to stopcocks positioned proximal and distal to the valve in the chamber and attached to a Hewlett-Packard PolyViso recorder. The system was filled with a blood analogue fluid consisting of 36.7 per cent glycerine solution in water. Flows across the valve were progressively increased at graded intervals by means of a Sams roller pump and the pressure difference recorded on paper with a direct ink stylus. Results Aortic valves obtained from subhuman primate donors. The correlation between aortic annulus size, species, and weight of the animal is shown in Table I. The aortic annulus size was found to be more dependent upon the weight of the donor animal than on the species. Aortic valves obtained from human autopsy donors. Correlation between the aortic annulus size, weight, and age of the patient from whom the fresh human hearts were obtained is shown in Table II, and correlation between age and aortic and mitral annulus size in normal human hearts fixed in formalin is shown in Table III. Examination of the aortic valve specimens obtained from primate donors, both human and subhuman, revealed anatomic features which made them more favorable for the construction of small size valve substitutes than is the case with grafts obtained from alternate donor sources, such as pigs and calves, which were examined in preliminary studies. The ridge of cardiac muscles so prominent beneath the right coronary cusp in the pig and calf hearts was noted to be virtually nonexistent in the trimmed aortic valves
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Table II. Correlation between patient's age and the aortic annulus size in normal hearts of infants and children* Age
Weight
1 day 7 days 10 days 1 'A mo. 2'/2 mo. 10 mo. 11 mo. lyr. 2yr. 3yr. 3 7 / 1 2 yr. 38/i2 yr. 3"/i2 yr. 4 6 /i2 yr. 5yr. 5u/i2yr. 76/i2 yr. 8 yr. 8V12 yr. 9"/i2 yr. 12 yr. 15 yr.
(lbs.)
8.0 7.0 8.0 9.5 8.6 16.0 19.8 23.0 24.0 29.5 46.0 20.0 37.5 41.8 52.0 37.5 44.0 56.0 66.0 59.0 43.0 84.0
ID of aortic valve annulus (mm.) 6.0 6.0 6.0 6.5 10.0 10.0 12.0 10.0 13.0 13.0 12.0 12.0 12.0 14.0 14.0 13.0 12.0 13.0 15.0 16.0 15.0 18.0
*Fresh autopsy specimens.
Table III. Diameter of aortic and mitral valve annulus in normal infants and children up to the age of 6 years * Age
Aortic (mm.)
Mitral (mm.)
0-1 wk. 1 wk.-6 mo. 6 mo.-l yr. 1-2 yr. 2-3 yr. 3-6 yr.
5-9 6-10 7-11 10-12 10-13 13-15
7-12 7-15 9-16 13-20 14-18 18-20
*Formaldehyde-fixed autopsy specimens.
obtained from both human and monkey donors (Fig. 2). Asa result the right coronary leaflet tended to fold back more completely against the aortic wall and was less obstructive to blood flow when mounted on a stent of small diameter. Assessment in a mock circulation The gradients developed across a series of primate aortic valves mounted on fabric-covered stent supports at varying flows in the in vitro duplicator system are shown in Fig. 3. The internal diameter represents the diameter of the mounted aortic valve whereas the external diameter represents the outside diameter of the
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l/min
Fig. 3. Gradients developed across primate aortic valves (rhesus and stumptail monkeys) mounted on fabric-covered stents at increasing flows in a mock circulation. ID, Internal diameter of mounted valve. OD, Outside diameter including 3 mm. sewing ring (tissue annulus).
5
Fig. 2. A, Appearance of a trimmed aortic valve obtained from a rhesus monkey. The internal diameter is 10 mm. B, The absence of a shelf of muscle tissue beneath the right coronary cusp is evident. completed prosthesis and includes a 3 mm. Dacron fabric sewing ring. The data indicate that the gradients which are developed are within an acceptable range at flow rates up to 3 L. per minute which occur in children during the first 5 to 7 years of life, as reported in the literature 6 " 8 (Fig. 4). The results of the flow studies carried out on dura mater valves mounted on fabric-covered stents are shown in Fig. 5. The internal diameter of the mounted completed tissue valve is virtually the same as that of the fabric-covered stent and represents the effective
6 7 8 9 » AGE (yeare)
II 12 13 14 15
Fig. 4. Cardiac output compared with age for normal children from birth to maturity (15 years). It can be seen that the normal cardiac output is less than 3 L. per minute during the first 5 to 7 years of life. orifice diameter of the valve. As can be seen, the flow characteristics of these valves are somewhat more favorable for a given size stent than is the case for primate aortic valves mounted on a stent of equivalent size, because of the absence of the aortic wall and annulus tissue which occupies space within the stent when an allograft or xenograft is mounted on a support (Fig. 6). Clinical experience Dura mater valves mounted on stents having a tissue annulus of 16 mm. were used to replace the mitral valve in 2 infants less than one year of age with
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mmHg
Fig. 5. Gradients developed across human dura mater valves mounted on fabric-covered stents at increasing flows in sizes I4 through 22 mm. Sizes reflect outside diameter of fabric-covered stent (tissue annulus). complete atrioventricular canal defects and mitral regurgitation. In both instances, satisfactory hemodynamic performance of the valve substitute has been demonstrated in the early postoperative period. Case reports CASE 1. K. T. (No. 83-91-67), a 7-month-old, 4.8 kilogram female infant with trisomy 21 and congestive heart failure since birth, underwent cardiac catheterization studies because of continued clinical deterioration. A complete atrioventricular canal defect with mitral regurgitation was demonstrated, together with a patent ductus arteriosus and pulmonary hypertension with equal pressures in the systemic and pulmonary arteries. The Qp/Qs ratio was 2.6. The patient was taken to the operating room on Jan. 27, 1976. With the infant under deep hypothermia, the ductus arteriosus was ligated and complete repair of the endocardial cushion defect was carried out with a Teflon fabric patch. The cleft mitral valve, deficient in leaflet tissue, was replaced with a 16 mm. dura mater valve. Following rewarming to normothermic levels the infant came off cardiopulmonary bypass without any difficulty. Simultaneous left atrial and left ventricular pressure measurements revealed a mean gradient across the dura mater valve of 2 to 3 mm. Hg and an end-diastolic gradient of zero. The left atrial pressure was 15 mm. Hg. The cardiac index was 1.7 L. per minute per square meter. One day following operation, the infant was doing well and was fully saturated with a central venous pressure of 10 mm. Hg, a left atrial pressure of 15, a pulmonary artery pressure of 30/27, and a systemic arterial pressure of 95/54 mm. Hg. There was no evidence of a residual intracardiac shunt. On the second day postoperatively, following extubation, the baby developed a mucus plug and sustained a respiratory arrest. Although resuscitated and hemodynamically stable following reintubation, she died from the neurologic and pulmonary consequences of this episode several days later. At autopsy the intracardiac repair was complete, the dura mater valve was clean and well placed, but severe bronchopneumonic changes were present in both lungs. CASE 2. A. H. (No. 85-18-06), an 8-month-old male infant weighing 6.8 kilograms, was admitted to the hospital. History and physical findings were consistent with the diag-
mmHg 16
# ODmm » Tissue annulus
Fig. 6. Comparison of gradients developed across human aortic valve and dura mater leaflet valve mounted on fabriccovered stent of comparable size at increasing flows. It is evident that, at comparable flows, the gradient is less for the dura mater valve. This reflects an increased effective orifice size for a given tissue annulus size when using a dura mater valve. nosis of pneumonia and congestive heart failure in the presence of an atrioventricular canal defect. Following appropriate medical therapy with antibiotics, digitalis, and diuretics, cardiac catheterization was carried out confirming the presence of a complete atrioventricular canal, pulmonary artery pressure at systemic levels, severe mitral regurgitation, and a left ventricular end-diastolic pressure of 15 mm. Hg. The Qp/Qs ratio was 2.6. The chest x-ray film revealed marked cardiomegaly (Fig. 7, A). On Jan. 29, 1976, he was taken to the operating room. With the infant under deep hypothermia, a complete atrioventricular canal defect with common atrium was repaired and the cleft mitral valve replaced with a 16 mm. dura mater valve. In the region of the ventricular crest the sewing ring of the valve was secured to the Teflon fabric patch which was tailored to reconstruct the ventricular and atrial septum. The patient was rewarmed to normothermic levels and came off
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Fig. 7. Chest x-ray films of an 8-month-old infant with complete atrioventricular canal defect and severe mitral regurgitation (A) preoperatively and (B) following insertion of a 16 mm. dura mater mitral prosthesis. bypass without any difficulty. Atrioventricular dissociation was present necessitating the use of a pacemaker. The mean left atrial—left ventricular pressure gradient across the valve was 4 to 5 mm. Hg at a heart rate of 110 beats per minute. On thefirstpostoperative day, the cardiac index was 4.6 L. per minute per square meter. He was extubated without difficulty and had no evidence of a residual shunt. The 16 mm. dura mater valve appeared to be functioning satisfactorily, and the infant has shown progressive clinical improvement postoperatively (Fig. 7, B). Discussion As the capabilities for operating on neonates, infants, and small children with severe forms of congeni-
The Journal of Thoracic and Cardiovascular Surgery
tal heart disease continue to be refined further, the need for improved heart valve substitutes for use in this type of patient population becomes more pressing. Included in this group are infants born with congenital aortic stenosis, mitral stenosis associated with parachute mitral valve, endocardial cushion defects, truncus arteriosus, and other anomalies. Although a considerable clinical experience with older children requiring heart valve replacement has been accumulated to date, valve replacement in the infant and young child remains more limited.9-12 It is likely that, if an improved family of valve substitutes were available for use in small hearts with a diminutive annulus, many more infants with congenital valvular lesions such as truncal valve insufficiency or mitral valve insufficiency associated with endocardial cushion defects could be referred for surgical therapy. Although in the latter instance valvuloplasties sometimes render the valve competent, this is not always possible. Even if acceptable valve substitutes in smaller sizes become available for this very young population, valve replacement would have to be considered a palliative procedure. In most instances it is likely that the valve will be outgrown and have to be replaced at least once before the patient reaches maturity. On the other hand, a significant number of adult patients in whom earlier vintages of prosthetic heart valves had been implanted have now undergone repeat valve replacement without undue difficulty and at an acceptable operative mortality rate, so that this concept seems more readily acceptable at the present time than it was several years ago. Of course, the younger the child is at the time of initial valve replacement, the more likely it is that at least one additional valve replacement operation will have to be carried out before adulthood, both by virtue of growth and by virtue of durability problems. Although concern has been expressed about the lack of growth of the annulus if a prosthesis of fixed ring size is inserted early in life, studies in our laboratory in the past suggest that this may not necessarily be a problem. Prosthetic ball-valve prostheses inserted in 6-week-old calves weighing 140 pounds at the time of initial operation were examined 1 to 3 years postoperatively at the time of full growth and when the animals' weight had increased to over 1,000 pounds. The hearts and periannular tissue had dilated sufficiently so that it would have been possible to insert a larger prosthesis at this time had this been necessary.13 Furthermore, techniques for enlarging the aortic annulus have recently been described and are being used clinically with success.14, 15 It is appreciated that the use of fresh donor tissue has
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certain advantages from the point of view of cell viability and possibly the durability of the leaflet substance. However, the practical problems of maintaining a storage bank of valve substitutes for use in children dictates that it is essential to employ a technique which allows for storage of the material for considerable periods of time. While the number of children requiring heart valve replacement is increasing as our techniques of diagnosis and surgical therapy improve, the incidence of very young children requiring valve substitution in any one institution remains relatively small over a given period of time. Thus the techniques of preservation explored in this study were those which allowed for reasonable storage periods for the completed valves. The techniques of preservation selected were those which have already been shown in clinical practice to be associated with acceptable periods of durability of up to 5 years.2, 16 Analysis of the tissue annulus size of several models of prosthetic heart valves currently available suggests that for the most part they are too large to use in many infants and children requiring heart valve replacement during the first few years of life. Bioengineers have indicated that it is not practical or feasible to decrease the size of the valves of the conventional design any further, using techniques currently available, without compromising hydraulic function to an unacceptable extent. In order to design heart valve substitutes of the order of magnitude which would be appropriate for the annulus size of the very small child, it was felt desirable to use tissue valves of central flow design known to be relatively nonthrombogenic and at the same time having a low profile suitable for use in a small cardiac chamber. Additionally, a valve substitute with flexible tissue leaflets would be expected to open and close more efficiently at the more rapid rates which are normal in infancy and early childhood than would a prosthetic valve relying on the motion of a central ball occluder or tilting disc to effect full opening and closing. The sewing ring of an artificial valve serves a dual purpose: Not only is it used to fix the valve to the annulus but, because of its padding effect, it also decreases the likelihood of a perivalvular leak. However, in the case of children with very small tissue annuli, the hemodynamic price paid for the presence of a generous buffer zone increases significantly as the annulus size decreases. The greater the space used up for frame, stent, and tissue, the less the space left for an effective orifice through which blood can flow. In many adults requiring prosthetic heart valve replacement, there is considerable annular calcification sec-
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ondary to atherosclerotic or rheumatic heart disease, and the need for a generous cushion seal provided by the sewing ring becomes quite important in securing the valve to the heart. On the other hand, most young children requiring heart valve replacement tend to have annuli which are quite pliable. This negates many of the benefits anticipated from the use of the oversized sewing ring present on many commercially available valves at the present time. The results of the studies carried out in a mock circulation employing tissue valves of small diameter mounted on fabric-covered stent supports revealed that it is possible to develop a valve substitute with a sewing ring in the 12 to 20 mm. size range which allows for adequate blood flow without the development of a significant gradient for flow requirements normal during the first few years of life. Since, in vivo, the diastolic filling period and systolic ejection periods occupy only a portion of each cycle, the instantaneous flow is higher than minute flow. However, in infants and children the relationship between cardiac output and body surface area is such that the gradients will still fall in the acceptable range when the small-sized valves are used. Thus acceptable hemodynamic palliation can be anticipated at least for several years in the very young patient following the insertion of such a valve. The hemodynamic studies described in this report tend to support the impression that there is an advantage to constructing the leaflet portion of the valve of tissue such as dura mater instead of using an allograft or xenograft aortic valve. However carefully the aortic valves are trimmed, the space consumed by the interposition of the residual aortic wall and annulus within the stent support limits the effective orifice remaining for the egress of blood. When sheets of dura mater are used to construct the valve, the diameter of the effective orifice approaches that of the fabric-covered stent support, eliminating this factor. In valves having a tissue annulus diameter greater than 24 mm. this is probably less of a practical consideration. Above this size, xenografts mounted on stent supports have been shown to function quite satisfactorily at the cardiac outputs predicted for most patients requiring heart valve substitution.17' 18 However, below 24 mm., and especially in the tissue annulus size range anticipated in many infants and young children requiring valve substitution (i.e., 12 to 18 mm.), this factor became more progressively significant if unacceptable stenosis is to be avoided postoperatively.19 On the other hand, it becomes technically more difficult to fashion competent trileaflet valves from sheets of tissue in sizes less than 14 mm.
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Initially, a number of species of animals were explored as potential donors for construction of the small sizes of valves. Ultimately, the primates were selected to serve as donors. It was found that in the size range required for this study the aortic wall tended to be thinner than that found in dogs, sheep, pigs, or calves. At the same time, the muscular ridge present beneath the right coronary cusp was less pronounced in primates and so allowed for improved flexibility of the leaflet occupying this third of the valve circumference. An additional advantage associated with the use of a tissue valve relates to its low incidence of thromboembolic complications in patients not receiving anticoagulants. While review of the literature to date indicates that complications, particularly hemorrhagic, do occur because of the increased physical activity of most children and the associated increased risk of trauma, the desirability of developing a heart valve substitute which does not require permanent anticoagulation becomes more attractive in the very young. It was for this reason, together with the bioengineering limitations already mentioned relating to the development of improved rigid valve designs in the very small size, that the thrust of the present developmental effort in this institution was directed toward finding improved tissue valve substitutes in the very small dimensions required. REFERENCES 1 Puig, L. B., Verginelli, G., Belotti, G., Kawabe, L., Frack, C. C. R., Pileggi, F., Decourt, L. V., and Zerbini, E. J.: Homologous Dura Mater Cardiac Valve, J. THORAC. CARDIOVASC. SURG. 64: 154,
1972.
2 Puig, L. B., Verginelli, G., Iryia, K., Kawabe, L., Bellotti, G., Sosa, E., Pileggi, F., and Zerbini, E. J.: Homologous Dura Mater Cardiac Valves, J. THORAC. CARDIOVASC. SURG. 69: 722,
1975.
3 Ionescu, M. I., and Ross, D. N.: Heart Valve Replacement With Autologous Fascia Lata, Lancet 1: 335, 1969. 4 Ionescu, M. I., Ross, D. N., Deac, R. C , Wooler, G. H.: Heart Valve Replacement With Autologous Fascia Lata, J. THORAC. CARDIOVASC. SURG. 60: 331,
1970.
5 Bartek, I. T., Holden, M. P., and Ionescu, M. I.: Frame-Mounted Tissue Heart Valves: Technique of Construction, Thorax 29: 51, 1974.
6 Jacob, W.: The Relation Between Cardiac Output and Body Size, Br. Heart J. 25: 425, 1963. 7 Jegier, W., Sekely, P., Auld, A. M., Simpson, R., and McGregor, M.: The Relation Between Cardiac Output and Body Size, Br. Heart J. 25: 425, 1963. 8 Rudolph, A.: Congenital Diseases of the Heart, Chicago, 111., Year Book Medical Publishers, Inc. 9 Robinson, G., and Young, D.: Secondary Implantation of a Mitral Valve Prosthesis in a Child, Ann. Thorac. Surg. 2: 208, 1966. 10 Young, D., and Robinson, G.: Successful Valve Replacement in an Infant With Congenital Mitral Stenosis, N. Engl. J. Med. 270: 660, 1964. 11 Castaneda, A. R., Nicoloff, D. M., Moller, J. H., and Lucas, R. V.: Surgical Correction of Complete Atrioventricular Canal Utilizing Ball Valve Replacement of the Mitral Valve, J. THORAC. CARDIOVASC. SURG. 62: 926,
1971. 12 Blieden, L. C , Castaneda, A. R., Nicoloff, D. M., Lillehei, C. W., and Moller, J. H.: Prosthetic Valve Replacement in Children: Results in 44 Patients, Ann. Thorac. Surg. 14: 545, 1972. 13 Detmer, D. E., and Braunwald, N. S.: Long-Term Fate of Autogenous Tissue Coverings on Prosthetic Heart Valves, Ann. Surg. 173: 139, 1971. 14 Konno, S., Imai, Y., Iida, Y., Nakajima, M., and Tatsuno, K.: A New Method for Prosthetic Valve Replacement in Congenital Aortic Stenosis Associated With Hypoplasia of the Aortic Valve Ring, J. THORAC CARDIOVASC SURG. 70: 909,
1975.
15 Wittig, J., McConnell, D., Buckberg, G., and Mulder, D.: Aortic Valve Replacement in the Young Child, Ann. Thorac. Surg. 19: 40, 1975. 16 Zuhdi, N., Hawley, W., Voehl, V., Hancock, W., Carey, J., and Greer, A.: Porcine Aortic Valves as Replacements for Human Heart Valves, Ann. Thorac. Surg. 17: 479, 1974. 17 Horowitz, M. S., Goodman, D. J., Fogarty, T. J., and Harrison, D. C : Mitral Valve Replacement With the Glutaraldehyde-Preserved Porcine Heterograft, J. THORAC CARDIOVASC. SURG. 67: 885,
1974.
18 Mclntosh, C. L., Michaelis, L. L., Morrow, A. G., Itscoitz, S. B., Redwood, D. R., and Epstein, S. E.: Atrioventricular Valve Replacement With the Hancock Porcine Xenograft: A Five-Year Clinical Experience, Surgery 78: 768, 1975. 19 Schultz, D. M., and Giordano, D. A.: Hearts of Infants and Children, Arch. Pathol. 74: 78, 1962.