Cardiothoracic surgery in the Antipodes

J

THoRAc CARDIOVASC SURG

78:804-822, 1979

Honored Guest's Address

Cardiothoracic surgery in the Antipodes Including a report of a randomized trial of medical and surgical treatment of asymptomatic patients with severe coronary artery disease; a long-term follow-up of both fresh and antibiotic-treated homograft valves; and some observations on glutaraldehyde-preserved valve tissue Brian G. Barratt-Boyes, K.B.E., M.B., Ch.M., F.R.A.C.S., F.A.C.S. (Hon.), F.R.S.N.Z.,

Auckland. New Zealand

I

am very greatly honored to be present at this meeting as the Honored Guest of The American Association for Thoracic Surgery. When your President, my close friend John Kirklin, invited me I was at first uncertain whether I should accept, as my contributions to cardiac surgery have been small and your President has other friends who could fulfill the duties of your Honored Guest better than I. On further reflection, however, I did accept because in so doing I could not only share the honor with my many associates at Green Lane Hospital who have played an essential part in what is, after all, a team effort, but also I could pay tribute to my many friends in this Association who have contributed to my career. May I thank you all for sharing your knowledge and expertise with me. New Zealand is a small country which lies almost directly opposite the United Kingdom on the globe, and most of its Caucasian inhabitants have emigrated from there. It is for this reason that New Zealand and Australia have come to be known as "the Antipodes. " The Thoracic Unit at Green Lane Hospital, Auckland, New Zealand, was established in 1942 in what was a state hospital, by a chest physician, Dr. From Green Lane Hospital, Auckland. New Zealand. Read at the Fifty-ninth Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass .. April 30 to May 2. 1979.

804

Chisholm McDowell , and a general surgeon, Dr. Douglas Robb, who had developed skills in thoracic surgery as a result of frequent visits to centers in this country. Churchill, Blalock, and Clagett were among his many American friends. Douglas Robb was also interested in vascular surgery, and under his guidance the Thoracic Unit at Green Lane developed into the major cardiovascular and thoracic department in the country, larger, in fact, than any of a number of units in Australia. Although in more recent years two additional cardiac units have been established, we continue to handle the great majority of cardiac surgery in New Zealand, which has a population of approximately 3 million. In effect, we have a captive medical population which, in combination with a state-financed hospital service, allows detailed and virtually complete follow-up of all our patients. The nature of our surgical practice is displayed in Table I, which lists all operations performed during 1976. This has been selected as a representative recent year, prior to the introduction of cardioplegic techniques. The thoracic operations include pulmonary and esophageal procedures, and the vascular operations include operations for both central and peripheral disease, including carotid and mesenteric disease and renal and portal hypertension. The breakdown of operations for acquired disease is shown in Table II. The

0022-5223/79/120804+ 19$01.90/0 © 1979 The C. V. Mosby Co.

Volume 78 Number 6 December, 1979

Cardiothoracic surgery in the Antipodes

Table I. All operations performed at the Green Lane Hospital Cardio-thoracic Surgical Unit during 1976 No. of operations Cardiac operations Congenital disease Acquired disease Thoracic operations Vascular operations Total

Diagnosis

I

VSD Tetralogy of Fallot Simple TGA Complex TGA TAPVC DORY and pulmonary stenosis Pulmonary atresia and VSD Truncus arteriosus A-P window Aortic stenosis Pulmonary stenosis Tricuspid atresia Ebstein's anomaly with pulmonary atresia Total

"k

107 .625 202 285

8 16 3 7

8.5 2.6 1.4 2.6

1,219

34

2.8

Table II. Analysis of the cardiac operations performed for acquired diseases at Green Lane Hospital during 1976 Hospital deaths Reason [or operation

No. of operations

Table III. Operations performed in infants less than 24 months of age at Green Lane Hospital during 1976

Hospital deaths No.

No.

I

"k

Acquired valvular disease Coronary vein graft Left ventricular aneurysm Pacemaker insertion or replacement Miscellaneous

212 255 6 126

5 6 0 I

2.4 2.3 0 0.8

26

4

15.4

Total

625

16

2.6

valvular procedures include single and multivalvular operations with or without coronary vein grafting. Coronary vein grafting was done for patients with all variants of angina and for some with congestive heart failure and low ejection fractions. In 1976, 107 patients were operated upon for congenital heart disease with eight deaths. Six of these deaths occurred among the 44 infants less than 24 months of age undergoing corrective operation (Table III). Therefore, our surgical practice is comparable to yours. We have a high incidence of coronary artery disease, with a male death rate from ischemic heart disease of 288/100,000. This compares with the figure of 381/100,000 (1971 to 1972) for the United States. This incidence of disease is reflected in a rapid increase in the numbers of coronary vein graft procedures performed each year (Fig. I). In addition, we have an increasing native Polynesian population. Auckland is the largest Polynesian city in the world, 110,000 of its 800,000 people being either indigenous Maoris or immigrant islanders mainly from the Cooks, Tonga, and Samoa. These people are very susceptible to rheumatic fever. They contract florid rheumatic valvular disease relatively early in life and

805

I No. I 10 II

Hospital deaths

o o

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3

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I I 2 I I I I 2 I 44

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Legend: VSD, Ventricular septal defect. TGA, Transposition of the great

arteries. TAPVC, Total anomalous pulmonary venous connection. DORV. Double-outlet right ventricle. A-P. Aortopulmonary.

often have multivalvular damage. They are a charming people, quite incapable of taking any medication regularly, such as prophylactic penicillin or postoperative anticoagulants. They constitute a disproportionately large number of our patients requiring operation for valvular heart disease. When prosthetic valves are used, they exhibit an alarmingly high thromboembolic incidence. These are the patients who have convinced the cardiologists and surgeons at Green Lane Hospital of the real need for a tissue valve which does not necessitate long-term anticoagulant therapy. For the remainder of my address, I would like to talk first about surgery for coronary artery disease. I will then discuss the long-term follow-up of homograft aortic valves and finally the behavior of glutaraldehydetreated valve tissue.

Coronary artery disease There is now no doubt that aorta-coronary saphenous vein grafting is highly effective in relieving anginal pain. It is therefore recommended in patients with significant angina which cannot be relieved by beta blockers or other medication. The evidence that aortacoronary saphenous vein grafting will prolong the life of patients, in addition to relieving their pain, is incomplete. There are still some doubts, engendered in part by the improved survival in patients receiving medical treatment, or no treatment at all, in this decade compared with the last. The follow-up of our own series of patients operated upon in the years 1972 to 1974 exemplifies this dilemma (Fig. 2). We have tried to match our patients

The Journal of

806

Barratt-Boyes

tf)

Thoracic and Cardiovascular Surgery

400

400

300

300

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200

100

100

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Fig. l. Numbers of aorta-coronary saphenous vein grafts (including internal mammary artery grafts) performed each year at Green Lane Hospital (isolated and combined procedures). with those included in the Veterans Administration (V A) cooperative randomized study of men treated for chronic stable angina pectoris over the same time interval. 1 Left main lesions are excluded from both series. Whereas our hospital mortality rate was half that of the VA patients, at the 4 year mark our survival rate was only 5% better than that for the medically treated patients in the VA trial, a difference which is too small to be highly significant. In patients with pain, this question of prolonged survival is really of secondary importance. The operation is indicated for the relief of symptoms, for which it is highly effective. However, the dilemma is vastly different when we are presented with a patient with severe coronary artery disease but no pain. Is operation indicated on the basis of the angiocardiographically demonstrated lesions? In an attempt to answer this very important question, a prospective study has been carried out at Green Lane Hospital to compare the medical management and surgical management of male patients who have recovered from two myocardial infarctions or more. The study was commenced in 1972 in the light of knowledge from studies at our hospital that the mortality rate for patients who had had recurrent myocardial infarction was 30% to 50% at 3 years" and that coronary artery operation for these patients would carry a relatively low risk. This is a preliminary report of the findings. All male patients under the age of 60 years who had had two myocardial infarctions or more, documented

by enzyme rise or electrocardiographic change or both, were considered for the trial. All patients who entered this study underwent coronary angiography and left ventriculography within 3 months of the second infarction. From assessment of these results, patients who had significant coronary artery disease and whose coronary anatomy was judged as suitable for aorta-coronary saphenous vein grafting, but who were asymptomatic or had only mild angina, were randomized into two groups. One group was managed conservatively and the other by coronary artery bypass. Some patients were not randomized because they had significant symptoms or because of the angiographic findings. They were placed in either an elective surgical or elective medical group. A total of 172 patients (Fig. 3) had had two or more myocardial infarctions. Thirty-five were not investigated. Fourteen of them had had severe congestive heart failure, 12 refused study, and nine had intercurrent disease. A total of 137 patients underwent coronary angiography. Of these, 87 were randomized into surgical and medical groups. All the randomized patients had no more than mild angina and had significant coronary artery disease but were otherwise "goodrisk" patients. Sixteen patients had elective coronary bypass, two for significant left main stem disease and 14 for disabling angina. Thirty-four patients had elective medical management. Two of them had normal coronaries, one had minimal coronary artery disease, and 3 I were turned down for randomization because of

Volume 78

Cardiothoracic surgery in the Antipodes

Number 6 December, 1979

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Fig. 2. Actuarial analysis of patient survival following coronary vein grafting (CVG) at Green Lane Hospital (GLH) between 1972and 1974compared with the Veterans Administration (VA) cooperative randomized study. I See text. CHF. Congestive heart failure. unfavorable coronary artery disease, usually poor distal vessels combined with poor left ventricular function. The threshold for randomization for these asymptomatic patients was higher than is our usual practice for patients with symptoms. As will be seen, two of these patients who subsequently began having symptoms then had elective operation. Fig. 4 shows the ejection fraction in each of the four groups studied." The number of patients in each group is given. Five patients in the trial surgical group had ejection fractions of 30% or less, but there is no statistical difference between the two randomized groups. Patients in the elective surgical group have comparable ejection fractions to those in the randomized groups. Note that just under half of them have ejection fractions within the normal range (>50). In the elective medical group, the ejection fractions help to differentiate between the two types of patients in this group, that is, those with normal coronary arteries and those unsuitable for operation because of poor ejection fractions (combined usually with distal coronary artery disease). The arrows in Fig. 4 refer to patients who experienced disabling angina after they had been placed in either of the medical groups and who subsequently underwent coronary artery operation because of the development of disabling angina. Only one of these eight crossover patients has died (at the time of operation). When statistical analysis is being done, crossover patients are considered to be in the medical group until the time of operation, when they enter the elective group.

The open circles on the graph (Fig. 4) represent patients who have died. Only two of the 17 deaths have occurred in patients with a normal ejection fraction. (Both occurred in trial surgical patients.) Among the patients treated medically, death has occurred only in patients with an ejection fraction less than 50%. In other words, no medically treated patient with a normal ejection fraction has died. This relation between mortality rate and ejection fractions in the medically treated patients, all of whom have had recurrent infarction prior to entering the study, is statistically significant (p < 0.01). The myocardial score in the four groups is shown in Fig. 5. Myocardial score:' is an improved version of the angiographic score devised by Friesinger, Page, and Ross" in 1970. It is an expression of the severity of coronary arterial obstructive disease which takes into account not only the severity of the obstruction but also the amount of myocardium supplied by each involved vessel. The left ventricular myocardium is given a fixed 15 units. Patients with normal coronary arteries have a score of O. With all coronary arteries occluded the score is IS. A score of 10 is approximately comparable with significant triple vessel disease. The randomized surgical and medical groups are more closely comparable when their myocardial scores are considered. Note that despite a history of recurrent infarction, one third of the trial surgical and trial medical patients have a score less than 10 (i.e., double or single vessel disease). Only three of the 16 patients treated surgically because of

808

The Journal of Thoracic and Cardiovascular Surgery

Barratt-Bayes

t-m INVESTIGATED Severe CHF Refused

In1ercuTent disease

35 14 12 9

RECURRENT MYOCARDIAL INFARCllONS "TOTAL 172

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severe angina (elective surgical) had a score less than 10. In contrast to the ejection fraction, there is no correlation between mortality and myocardial score. The actuarial life table showing survival for the randomized medical and surgical groups is shown in Fig. 6. The average follow-up was 3.4 years, Survival is good in both groups. It is slightly better in the medical group (87%) than in the surgical group (82%), but these differences are not significant. There have been four deaths in the medical group, all from cardiac causes, and six in the surgical group, Only one of these was perioperative (a hospital mortality rate of 2.4%), and three of the late surgical deaths were cardiac. One late death was due to carcinoma and the other occurred while the patient was awaiting operation. If these last two patients are excluded from the analysis of the surgical deaths, the survival rates in the medical and surgi-

cal groups is almost identical. This, then, is the important finding in this trial to date. That is, with good-risk male patients less than 60 years of age who are free of significant symptoms after recurrent myocardial infarctions, there is no demonstrable improvement in survival after 4 years between conservative and surgical management. A more recent analysis to be reported in detail elsewhere shows no advantage after 5 years. The strikingly good survival rate of the trial medical patients (87%), who had no more than mild pain, is very similar to that of the medically treated patients in the VA trial who had chronic stable angina (90%). Their survival is not due to propranolol therapy, as only two of our 45 patients were receiving this drug. An additional finding of interest is that the incidence of further myocardial infarctions also has been similar in the two groups. Therefore, the operation does not seem to have given

Volume 78 Number 6 December, 1979

Cardiothoracic surgery in the Antipodes

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added protection against further infarction. These statements presuppose that those medically treated patients in whom severe angina developed, and there were six in the trial medical group, underwent operation at this time with no deaths. There has been one death in the elective surgical group, which includes the eight crossover patients (Fig. 6). The elective medical group has predictably shown a lower survival rate of 74% at 4 years. However, this is considerably better than was originally anticipated. The next graph (Fig. 7) was drawn to show again the interesting finding that the medically treated patients in our series have survival figures better than were originally anticipated. Survival of patients with myocardial scores greater than 10 from both medical groups in our study are compared with survival of patients with triple vessel disease treated medically at the Cleveland Clinic between 1963 and 1965 and reported by Bruschke and associates'; in 1973. It is impossible to say whether selection played an important part in producing this marked difference, but theoretical explanations include the different decade of the study, reduced smoking habits of our patients, and the fact that our patients were asymptomatic, whereas in the Cleveland Clinic series the patients generally were studied for symptoms. In the Cleveland study, however, a history of myocardial infarction was regarded as a bad prognostic feature. In both series significant left main disease has been excluded. As already noted, the good survival of our medically treated patients at 4 years is very similar to that reported recently from the VA trial, I and it

8 10

The Journal of Thoracic and Cardiovascular

Barratt-Boyes

Surgery

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suggests that the mortality rate from coronary artery disease is less in this decade than it was in the previous decade. These medical survival data emphasize how erroneous it would have been to have compared the survival of our surgically treated patients with that of the Cleveland Clinic patients. The lowest curve in Fig. 7 shows the survival of the patients with recurrent infarct from Auckland Hospital studied between 1966 and 1967 and reported by Norris and associates." It was this poor survival that led us to select patients with recurrent infarction for a trial of surgical treatment as it seemed likely that the benefits of operation would become apparent very quickly. However, these patients were not studied angiographically, and the group included many who were unsuitable for both angiography and operation. In fact, the highest mortality rate occurred in those patients unsuitable for angiography because of congestive heart failure or other important disease. This difference is shown in Fig. 8. The 5 year survival for the investigated patients was 80% and the 3 year survival for the uninvestigated patients was 40%. In summary, this randomized trial compares conservative and surgical management in male patients with two or more documented myocardial infarctions who remained asymptomatic and who were considered good-risk surgical candidates. The study shows no advantage with regard to either survival or subsequent

myocardial infarction following surgical treatment. In other words, despite the demonstration of triple vessel disease in the majority of these patients, survival has been no better with surgical than with medical management. At the moment we do not have complete data giving the incidence of graft patency in the surgical group. Perhaps the most striking finding of all is the excellent survival in the trial medical group. It is uncertain whether these results can be applied to asymptomatic patients who have had a single myocardial infarction or no infarction. Currently, we also are randomizing patients after a single myocardial infarction, but the data are not yet sufficient for meaningful analysis.

Homograft valve follow-up The homograft valve is still used fairly extensively in the United Kingdom and also at Green Lane Hospital, but it has been abandoned in the United States. Is there justification for its continued use, particularly with the more recent introduction of the glutaraldehyde-treated porcine aortic valve, which apparently has many of the advantages of a homograft? In an attempt to answer this question, I will look first at the original series of fresh homografts, work which was based upon the heterotopic transplants reported by Kerwin and colleagues.' The first operation was performed in August of 1962,

Volume 78

Cardiothoracic surgery in the Antipodes

Number 6

8I I

December, 1979

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YEAR OF FOLLDW-LP Fig. 8. Actuarial survival curves in 135 of the patients investigated by coronary angiography in the recurrent infarction project compared with those who were unsuitable for (or refused) investigation, and in the subsequent 20 months, 16 patients aged 14 to 62 years had a fresh homograft valve implanted. The valves had been removed under sterile conditions from donors of similar ages soon after death and had been stored in Hanks balanced salt solution at 4° C without antibiotics from I to 25 days prior to insertion. The storage time exceeded I week in only four of the 16. The double suture line technique employed, which involves inverting the valve into the left ventricle during placement of the lower ring suture line," was devised on theoretical grounds. It has worked well and has not been changed since Case I except for the later addition of vertical mattress sutures? which obliterate the dead space beneath the valve buttresses and contribute importantly to the abolition of perivalvular leaks. In these original 16 patients it is perhaps not surprising that there were some examples of iatrogenic incompetence either from a peripheral perivalvular leak or a central leak caused by imperfect valve placement. The data from this small series of patients are inevitably anecdotal but nevertheless are of interest and importance in assessing host response to implantation of a fresh "viable" valve-a true valve transplant. They are relevant also to the current use of homograft valves sterilized in antibiotics, which we will discuss shortly, and to the use of glutaraldehyde-treated tissue. Thirteen of the 16 patients have been recatheterized on 20 occasions during their follow-up (Fig. 9). No

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Fig. 9. Peak systolic gradients across the aortic homograft valve measured at postoperative cardiac catheterization in 13 patients at various time intervals. patient has shown a significant resting gradient, and repeat studies have not shown any increase in gradient. Leaflet calcification has been present at autopsy or reoperation in three specimens, 8, 12, and 13 years after implantation, but it was insufficient to produce any stenosis. 10

8 I2

The Journal of

Barratt-Bayes

Thoracic and Cardiovascular Surgery

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50

CAUSES OF INCOMPETENCE PERIVALVUu\R LEAK 1 ENDOCARDITIS 3 PROGRESSIVE AOOTIC ROOT DILATATION 3 CUSP RUPTURE 9 UNKNONN 2 TOTAL 18

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Volume 78

Cardiothoracic surgery in the Antipodes

Number 6 December, 1979

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Fig. 12. Actuarial analysis of significant homograft valve incompetence relative to aortic size and contour 9 years after implantation. Histologic examination of removed specimens has shown ingrowth of host tissue into most of these grafts, the ingrowth replacing the leaflet with new viable tissue to form a pliable leaflet several times thicker than the original. 11 This is in marked contrast to chemically treated homograft valves, in which there is no tissue ingrowth;" and also to glutaraldehyde-treated tissue, 1:1 in which the only host reaction is phagocytosis of the graft with or without calcification. The fate of the 16 fresh valves is shown in Fig. 10. In half of the patients the valve has continued to function for 12 years or more postoperatively, and in the other half it has not, for a variety of reasons. The eight in whom the valve did not continue to function can also be divided in half. In the first group of four, two died early from cardiomyopathy and myocardial infarction and two required reoperation for technical reasons. In all four of these patients the homograft leaflets were well preserved, These four patients are best excluded in assessment of long-term leaflet function. In the remaining four, leaflet failure from 3 to 9 years postoperatively produced moderate or severe incompetence. However, leaflet failure is only presumptive in the two who died, as neither was subjected to autopsy. In the two who were reoperated upon, death was due to leaflet rupture in one and leaflet shrinkage in the other, the cusps being virtually absent. We have never seen this latter feature in any other specimen. Both leaflet rupture and leaflet shrinkage are probably related to rejection.

In eight patients the valve continued to function at 12 years, Trivial incompetence has been present since operation and has remained unchanged in the first two. On the basis of criteria adopted by Stinson, Griepp and Shumway;':' these two patients would be considered to have valve failure. In fact, they remain entirely asymptomatic more than 14 years after insertion of the valve. In three further patients, trivial or mild incompetence appeared first 7 to 9 years postoperatively and, in one of these patients, has progressed to severe incompetence necessitating reoperation at 12 years. One patient has had moderate incompetence throughout his course because of a peripheral perivalvular leak, shown angiocardiographically, and is asymptomatic. Two patients have no aortic diastolic murmurs. These data indicate that in eight of 12 patients, or 75%, the fresh homograft valve has functioned for 12 years, and in seven it continued to function beyond that time. Whether these results are regarded as good or bad depends, I suppose, on one's philosophy. Clearly, the device is not perfect, and most if not all patients are going to require reoperation at some time in the future. The total absence of morbidity other than incompetence, together with freedom. from the need to take anticoagulants, makes this device competitive with others. Because of the difficulties associated with the collection of fresh homograft valves in sufficient numbers, this technique was abandoned in 1964 in favor of chem-

The Journal of

8 14

Barratt-Bayes

Thoracic and Cardiovascular Surgery

Fig. 13. Axial views of a 33 mm diameter Hancock valve photographed in the pulsatile flow tunnel at a range of flow rates. A. Zero flow. B. 2.4 L min-I. At this flow one leaflet only has opened. C, 3.7 L min-I. At this flow two leaflets have opened. The LIpper left leaflet shows marked kinking where it has flexed in the center of the belly rather than at the true hinge area. D. 8.8 L min-I. The third leaflet has opened but only slightly and with kinking. Even at this large flow the orifice size is far less than the valve ring diameter. ical sterilization, mainly with betapropiolactone. Although the early results with this chemical technique were good, longer follow-up revealed an unacceptably high incidence of leaflet failure from rupture. For this reason, antibiotic sterilization of homograft valves was introduced in 1968, and this technique has been in use since that time. Histologic examination of antibiotic-sterilized valve leaflets 15 indicates that there is a more pronounced host reaction than is the case with chemically sterilized valves. Thus the host intimal fibrous sheath does grow for varying distances along the leaflet, but ingrowth of tissue into the leaflet is minimal. 16 The host reaction is therefore less complete than with a fresh valve. What, then, are the results following insertion of an antibiotic-treated homograft valve in the aortic posi-

tion? These were last reported from Green Lane Hospital in 1976, when the follow-up was significant to 6 years. 17 The patients being followed comprised a consecutive personal series of patients in whom an unstented antibiotic-treated aortic homograft valve was inserted between August, 1968, when this technique was introduced, and December, 1970. The reason for following a personal series of patients was to minimize the incidence of postoperative incompetence caused by technical error, for this can be high in inexperienced hands and could overshadow the advantages of such a valve when accurately inserted freehand. We were interested primarily in the incidence of significant homograft valve incompetence for, as with a fresh homograft, this is the only morbidity associated with this device. At 6 years the actuarial incidence was

Volume 78 Number 6 December, 1979

9%. The curve indicated an almost linear increase in the incidence of significant incompetence without evidence of sudden valve deterioration. In searching for subgroups of patients who might behave differently, we found the lowest incidence of incompetence in patients with a small aortic root «24 mm) and the highest incidence in those with preoperative aneurysm or severe distortion of the aortic root or sinuses of Valsalva. These differences were statistically significant (p < 0.01). The high incidence in patients with a large aneurysmal root was related either to progressive dilatation of the aorta with overstretching of the valve so that the cusps could not meet centrally or, in one patient, to a perivalvular leak. Cusp rupture was also more common in these overstretched leaflets. We were unable to find any other significant correlations. 17 The most recent review of these same patients carries the follow-up to IO years, but the data are significant to only 9 years (Fig. II). The average follow-up of all patients up to the time of last review, late death, or reoperation is 6\4 years. For those patients still alive, the average follow-up is 8 years. Only five patients have been lost to follow-up. At 9 years, actuarial analysis indicates that 19% of patients have significant incompetence (that is, moderate or severe). If we remove from the analysis the 14 patients with aortic root aneurysm or severe distortion, for we now know that such patients are unsuitable for an unstented aortic homograft, the incidence is reduced to 14%. Again, the curve indicates an almost linear increase in the incidence. Progressive root dilatation or distortion accounts for four cases of significant incompetence and endocarditis accounts for three, whereas cusp rupture owing to leaflet wear was proved in only nine, or half the total (Fig. II). Reoperation was performed in 14 of the 18 patients. Re-examination of the differences between a small and aneurysmal aortic root (Fig. 12) shows even more striking differences than at six years. In those with a root diameter less than 24 mm there continues to be only one example of severe incompetence (caused by Candida endocarditis). This patient and two others have died, but the remainder are alive with perfect or nearly perfect valve function. It would therefore seem that the unstented antibiotic-sterilized homograft valve behaves best in the small aortic root. In fact, there is a 95% chance that it will continue to function normally 9 years postoperatively in patients with a root diameter less than 24 mm. This is fortunate, for this valve can be inserted into a small root without a significant gradient. In our view, it

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Fig. 14. Nomarski photomicrograph of wet tissue showing loss of normal collagen crimp in the body of the aortic leaflet of a Hancock valve. The (/''1'0\1' marks the site of a kink (x640). (From Broom ND, Thomson FJ: Thorax. 1979. published by British Medical Association House. edited by BB Milstein. A Seaton.) is the valve of choice in such patients. Fortunately, this includes most younger patients, particularly young child-bearing women in whom the lack of anticoagulants is a major advantage. Conversely, an unstented aortic homograft valve is unsuitable in patients with an aneurysm of the ascending aorta or a false or true aneurysm of the aortic root.

Glutaraldehyde-treated valve tissue Like others were have been excited by the demonstration, resulting from the pioneer work of Alain Carpentier, that glutaraldehyde fixation of valve tissue produces a reasonably durable prosthesis which does not require anticoagulants over the long term. We currently use the Hancock valve fairly commonly in the mitral position and, occasionally, when there is a larger aortic root, in the aortic position. Clearly, glutaraldehyde-treated tissue behaves dif-

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Fig. 15. Nomarski composite photomicrograph of wet tissue showing a Hancock leaflet free edge at kink sites (orig. mag. x 120). (From Broom NO, Thomson FJ: Thorax, 1979, published by British Medical Association House, edited by BB Milstein, A Seaton.) ferently from antibiotic-treated tissue in vivo. It is designed to be biologically inert so that tissue ingrowth does not. or should not, occur. The life of this bioprosthesis is therefore dependent entirely on the strength of the leaflet tissue. Thus, whereas with homograft tissue there may be a percentage of recipients in whom the valve becomes replaced by host tissue and will last indefinitely, with glutaraldehyde-treated tissue there is a definite end point when the tissue will fatigue and fracture. producing incompetence, or will become progressively stiffer and calcified. producing stenosis." What is known of the mechanical properties of glutaraldehyde-treated valve tissue? My colleagues and I have become increasingly involved in this area since we have been fortunate enough to interest two of our doctoral research colleagues in our University's department of mechanical engineering in this problem, Drs. Thomson and Broom. This work began with attempts to design a flexible plastic stent for use with aortic homograft valves, which tend to become deatched from the pillars of a rigid metal stent. Homograft valves differ in this regard from stented glutaraldehyde-treated tissue, which has not had this defect. Reis and co-workers IH had claimed in 1971 that the polypropylene Hancock stent had flexible struts that significantly lessened both leaflet stress and the likelihood of detachment of the glutaraldehyde-treated porcine valve from the stent pillars. In our laboratories, Thomson developed a prototype plastic stent using injection molding techniques. X-ray diffraction was used to examine the degree of molecular alignment achieved under different molding conditions. Both polypropylene and plastic with superior creep resistance properties not before used clinically, namely. acetal copolymer, were used for the manufacture of a 19 mm diameter stent suitable for implantation in the mitral position in large dogs. The stent struts were de-

signed to flex approximately I mm under physiological pressure loads when mounted with an aortic homograft valve. The uncovered stents were tested in the laboratory by means of a rig designed to assess the degree of strut creep under intermittent loading conditions. These tests indicated that polypropylene showed excessive creep whereas acetal copolymer did not. Homograft aortic valves mounted on these c1othcovered stents were implanted in the mitral position of dogs. The valves were removed after intervals of 5 to 18 months and tested in a pulsatile water tunnel. I!J These tests confirmed that the antibiotic-treated homograft leaflets open fully. The acetal copolymer stent struts showed a physiological degree of movement with valve closure and no strut creep. In contrast, the polypropylene stent showed marked strut creep after being in place for 8 months and was clearly unsuitable for clinical use. If this permanent deformation is to be avoided, the struts must be made much thicker and their degree of movement is then minimal. A Hancock valve mounted in the pulsatile water tunnel (Fig. 13) showed absence of strut movement, apart from very slight motion in one strut, and poor leaflet movement. The leaflets were stiff and often were bent near the center of the leaflet belly rather than at the true hinge area, so that there were actual kinks in the cusp at points of opening. At low flow rates. leaflet opening was minimal and the leaflets opened sequentially and suddenly. Clearly, the orifice diameter may bear little relationship to the stent diameter. It is likely that the areas of stasis which develop above the incompletely opened cusps are sites of fibrin and thrombus formation and explain the signi ficant embolic incidence with this device compared with the homograft. When the Hancock leaflets are examined microscopically, the striking feature is the complete loss of crimp in the collagen (Fig. 14). The fibers are virtually

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Cardiothoracic surgery in the Antipodes

Fig. 16. A series of low-power photomicrographs taken of longitudinal slices of glutaraldehyde-preserved heart valve tissue to show how increasing compressive flexure of fatigued tissue (A through C) opens up large cavities on the compression (concave) side of the leaflet (orig. mag. x35). (From Broom ND: J THoRAc CARDlOVASC SURG 76:202. 1978. published by The C. V. Mosby Company.)

Fig. 17. An advanced stage of fatigue disruption in glutaraldehyde-preserved valve tissue prepared by standard histologic techniques (orig. mag. x35). (From Broom ND: J THoRAc CARDlOVASC SURG 76:202. 1978. published by The C. V. Mosby Company.)

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100 MM Hg.

Fresh

l4hrs

~

~

100

(f) (f)

J4hrs

STRESS

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tn

gm/mm 2 (loading)

168hrs

50

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4 STRAIN

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Fig. 20. Representative stress-strain curves for tissue specimens removed from leaflets of valves fixed in glutaraldehyde at 100 mm Hg and from all three leaflets of a single Hancock valve. (From Broom ND. Thomson FJ: Thorax. 1979. published by British Medical Association House. edited by BB Milstein. A Seaton.)

Fig. 18. Engineering stress-strain curves for fresh and glutaraldehyde-preserved (0.625'10 solution) aortic valve tissue. See text.

1-25 hrs

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Fig. 19. Stress-strain curves of valve tissue during fixation in 0.625'7c glutaraldehyde (in 0.15M phosphate buffer at pH 7.2) cycled at 30 Hz in Ringer's solution at 37° C.

straight-this is quite abnormal, as the collagen should show a prominent crimp. Fig. 14 and subsequent illustrations showing microscopic features were photographed by means of Nomarski interference contrast. which enables the collagen to be imaged directly in its wet state. 20 The tissue is not otherwise preserved, stained, fixed in paraffin. or cut with the microtome. Thus it is undistorted. Moreover, Broom has been able to conduct mechanical stress-strain measurements in the same strips of valves shown microscopically in these illustrations by using a microtensile straining device which inserts directly onto the stage of an optical Nomarski contrast microscope. 21 In this way, the mechanical properties of the tissue can be correlated very closely with its collagen arrangement. Fig. 15 shows a composite Nomarski contrast view of a Hancock leaflet at the site of a kink. Note the distortion of the collagen arrangement. When glutaraldehyde-treated tissue is subjected to accelerated fatigue testing in vitro.P the collagen bundles gradually separate (Fig. 16) and finally fracture (Fig. 17) on the "compression" side of the leaflet, i.e., the concave aspect. Although such in vitro testing cannot be transferred directly to the clinical setting, the findings are almost certainly highly significant so long as the tissue does remain biologically inert when implanted. These changes are apparent after the equivalent of about I2 years in vivo, and one can postulate that they will be accelerated at sites of leaflet kinking. Must all glutaraldehyde-treated tissue possess these unfavorable features? Is there any way that it can be

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Fig. 21. Axial views of a valve fixed at I()() mm Hg for a range of steady forward flow rates in liters per minute as flows. a, 0 Umin. b. 0.3 c. 1.2 d. 2.3 e, 3.3/, 5.0 g, 6.911, 9.1. The leaflet numbers are marked in a . Leaflet I remains almost fully closed up to flows of 3.3 Umin and then opens completely in a single movement at some flow rate less than 5 Umin. Leaflet 2 is closed up to a flow of 2.3 Umin and then opens progressively. Leaflet 3 is the first to open but shows marked kinks (arrows]. (From Broom NO. Thomson FJ: Thorax. 1979. published by British Medical Association House. edited by BB Milstein. A Seaton.)

improved? Before completing this account, I must describe engineering stress-strain curves (Fig. 18). Stress or loading is on the vertical plane and strain or deformation is on the horizontal plane. Looking first at fresh homograft valve tissue, note that with minimal loading there is a large deformation (the flat portion of the curve) corresponding to the considerable change in shape of the leaflet to an open or closed position. This is followed by a "knee" in the curve and then a steep rise, indicating minimal further deformation as the load is further increased, The maximal deformation of fresh tissue lies between 20% and 30%, i.e., the length is increased over the original length by up to 30%. It is known that the flat or "incubation" period of the curve corresponds to take-up in the normal crimp of the collagen fibers. Thus when the deformation reaches 30% the fibers are almost straight. When the load is released the curve is reversed and the crimp returns. Clearly, then, collagen crimp is most important;" The four curves to the left in Fig. 18 are the result of glutaraldehyde treatment. The curves shift progressively to the left up to about 24 hours after immersion of the tissue in 0.625% glutaraldehyde; that is, the tissue becomes stiffer and the incubation period of the curve is largely lost. Broom'" also has found that when the glutaraldehyde-treated tissue is cycled at 30 Hz in Ringer's solution at 37° C, it becomes progressively more stiff (Fig. 19). The 234 hour curve corresponds to

about 9 months at a normal heart rate. These are features which are inherent in the glutaraldehyde fixing process and the collagen cross-linkage which it produces. Broom and Thomson, 2~ however, have discovered that the stress-strain curves are profoundly affected by the degree of crimp present in the leaflet at the time it is fixed in glutaraldehyde solution. The less the crimp the stiffer the tissue. The stress-strain curves of the Hancock valve leaflets which have no remaining crimp are shown in Fig. 20, There is virtually no change in length with increasing load, as the tissue is already fully stretched and very stiff. Note that the percentage strain scale is 0 to 4, whereas in Fig. 16 it is 0 to 40. This curve is comparable to our experimental porcine valves which were fixed in glutaraldehyde at a closing pressure on the leaflets of 100 mm Hg. Regrettably, we are not told how the Hancock valves are prepared. However, we can assume from these data that they are fixed under pressure. Like the Hancock valves, our valves fixed at 100 mm Hg pressure also open poorly (Fig. 21). At a flow of 1.2 L, only one leaflet has moved, and it is kinked at its free edge; at a flow of 2.3 L, two of the three leaflets still remain closed. On Nomarski contrast imaging, the leaflet shows a loss of crimp similar to that of the Hancock leaflet (Fig. 22). We have found that to preserve the collagen crimp in

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Fig. 22. Nomarski photomicrograph of interior belly of a leaflet fixed at 100 mm Hg showing loss of crimp (Orig. mag. x500). (From Broom NO. Thomson FJ: Thorax. 1979. published by British Medical Association House. edited by BB Milstein. A Seaton.)

Fig. 23. Nomarski photomicrograph of interior belly of a leaflet fixed at 0 mm Hg showing normal crimp (Orig. mag. x700). (From Broom NO. Thomson FJ: Thorax. 1979. published by British Medical Association House. edited by BB Milstein. A Seaton.)

almost normal form, both on the surface and in the substance of the cusps, it is necessary to fix the valve at near zero pressure. Fig. 23 shows such a leaflet fixed in glutaraldehyde. The leaflets were floated together at virtually zero pressure. They open in almost normal fashion without kinking, and at a 2 L flow all three leaflets are partially open (Fig. 24). The stress-strain curves from the leaflet fixed at zero pressure (Fig. 25) show significant improvement, with some incubation period in the curve, although there is still a shift to the left compared with the curve for the fresh leaflet. The strain scale here reaches 15%. The curves for valves fixed at a closing pressure of 4 mm Hg are also shown in Fig. 25. Clearly, even this low pressure produces significant stiffening of the cusps. In fact, there is some crimp present at this pressure (Fig. 26), but less than at zero pressure. In summary then, these findings indicate that function of glutaraldehyde-fixed leaflets is closely related to the pressure upon the leaflets at the time of fixation. Fixation at very low pressure may improve orifice size at low flow. It will also lessen leaflet kinking and, presumably, the stage at which disruption will ulti-

mately occur. Our preliminary experiments indicate that it is quite possible to obtain a completely competent valve with good leaflet coaptation by means of zero fixation pressure and thereby preserve the original collagen crimping structure. These findings with glutaraldehyde-treated tissue indicate that there is much still to learn about valve preparation and antibiotic treatment of homograft tissue. I believe that both types of tissue valves will play an important part in valve replacement operations in the future. In conclusion, Mr. President, may I thank you once again for this invitation, which has enabled me to present some of the material from my unit. To quote from Samuel Butler, a widely known writer and painter who died in 1902 and who spent some of his life in New Zealand: . The advantage of doing one's praising for oneself is that one can lay it on so thick and exactly in the right places. ,. The work reported here is the result of a team effort involving surgeons and cardiologists as well as many other personnel. The myocardial infarction trial was under the direction of Dr. R. M. Norris. Much of the follow-up was the direct responsibility of Shirley Hutchinson. Dr. Broom's and Dr.

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82 1

Fig. 24. Axial views of a valve fixed at 0 mm Hg for a range of steady forward flow rates in liters per minute as follows: a, 0 L/min. h. 0.1 c, 0.6 d. 1.2 e. 2.0j'. 3.0 g. 4.711, 6.5. All leaflets opened progressively from the onset of flow and without kinking. (From Broom NO. Thomson FJ: Thorax. 1979. published by British Medical Association House. edited by BB Milstein. A Seaton.)

- --4 MM Hg

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Fig. 25. Stress-strain curves from leaflets fixed in glutaraldehyde at a closing pressure of 0 and 4 mm Hg. The varying degrees of initial strain exhibited particularly by the 0 mm Hg tissue reflect differing degrees of complexity of fiber organization which add more or less stiffness to the original tissue. (From Broom NO. Thomson FJ: Thorax. 1979. published by British Medical Association House. edited by BB Milstein. A Seaton. ) Thomson's studies were financed by The Medical Research Council of New Zealand. REFERENCES Read RC. Murphy ML. Hultgren HN. Takaro T: Survival of men treated for chronic stable angina pectoris. A cooperative randomized study. J THoRAc CARDIOVASC SURG 75: I. 1978 2 Norris RM. Caughey DE. Deeming LW. Mercer CJ, Scott PJ: Coronary prognostic index for predicting survival after recovery from acute myocardial infarction. Lancet 2:485. 1970

Fig. 26. Nomarski photomicrograph of wet tissue showing appearance of collagen geometry in the interior belly of a leaflet fixed in glutaraldehyde at 4 mm Hg pressure. The crimp is much reduced (Orig. mag. x700). (From Broom NO. Thomson FJ: Thorax. 1979. published by British Medical Association House. edited by BB Milstein. A Seaton.)

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3 Bass NM, Whitlock RML, Vedler M, Partridge lB, Wattie Wl , Brandt PWT: Left ventricular volume estimation by single-plane right anterior oblique cineangiocardiography (in press) 4 Brandt PWT, Partridge lB, Wattie Wl: Coronary arteriography. Method of presentation of the arteriogram report and a scoring system. Clin Radiol 28:361, 1977 5 Friesinger GC, Page EE, Ross RS: Prognostic signi ficance of coronary arteriography. Trans Assoc Am Phys 83:78, 1970 6 Bruschke A VG, Proudfit WL, Sones FM lr: Progress study of 590 consecutive nonsurgical cases of coronary disease followed 5-9 years. I. Arteriographic correlations. Circulation 47:1147, 1973 7 Kerwin Al, Lenkei SC, Wilson DR: Aortic valve homograft in the treatment of aortic insufficiency. Report of nine cases, with one followed for six years. N Engl 1 Med

266:852, 1962 8 Barratt-Boyes BG: Homograft aortic valve replacement in aortic incompetence and stenosis. Thorax 19:131, 1964 9 Gonzales-Lavin L, Barratt-Boyes BG: Surgical considerations in the treatment of ventricular septal defect associated with aortic valvular incompetence. 1 THoRAc CARDIOVASC SURG 57:422, 1969 10 Barratt-Boyes BG, Roche AHG, Brandt PWT, Smith lC, Lowe lB: Aortic homograft valve replacement. A longterm follow-up of an initial series of 101 patients. Circulation 40:763, 1969 II Gavin lB, Barratt-Boyes BG, Hitchcock Gc, Herdson PB: The histopathology of "fresh" human aortic valve allografts. Thorax 28:482, 1973 12 Gavin lB, Herdson PB, Barratt-Boyes BG: The pathology of chemically sterilized human heart valve allografts. Pathology 4: 175, 1972 13 Spray TL, Roberts We: Structural changes in porcine xenografts used as substitute cardiac valves. Am 1 Cardiol

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Thoracic and Cardiovascular Surgery

14 Stinson EB, Griepp RB, Shumway NE: Long-term results of isolated aortic and mitral valve replacement with fresh aortic allografts, Second Henry Ford Hospital International Symposium on Cardiac Surgery. lC Davila, ed., New York, 1977, Appleton-Century-Crofts, p 502 15 Gavin lB, Herdson PB, Monro lL, Barratt-Boyes BG: The pathology of antibiotic-treated human heart valve allografts. Thorax 28:473, 1973 16 Barratt-Boyes BG: Long term follow-up of aortic valvar grafts. Br Heart 1 (Suppl) 33:60,1971 17 Barratt-Boyes BG, Roche AHG, Whitlock RML: Six year review of the results of freehand aortic valve replacement using an antibiotic sterilized homograft valve. Circulation

55:353, 1977 18 Reis RL, Hancock WD, Yarbrough

19

20

21

22

rw. Glancy DL, Morrow AG: The flexible stent. 1 THoRAc CARDIOVASC SURG 62:683, 1971 Pohlner PG, Thomson Fl, Hjelms E, Barratt-Boyes BG: An evaluation of aortic homograft valves mounted on flexible support frames and a comparison with glutaraldehyde-treated porcine valves. 1 THoRAc CARDIOVASC SURG 77:287, 1979 Broom NO: The observation of collagen and elastin structures in wet whole mounts of pulmonary and aortic leaflets. 1 THORAC CARDIOVASC SURG 75:606, 1978 Broom NO: Simultaneous morphological and stress-strain studies of the fibrous components in wet heart valve leaflet tissue. Connect Tissue Res 6:37, 1978 Broom NO: Fatigue-induced damage in glutaraldehydepreserved heart tissue. 1 THoRAc CARDIOVASC SURG 76:

202, 1978 23 Broom NO: The stress-strain and fatigue behaviour of glutaraldehyde-preserved heart-valve tissue. 1 Biomech

10:707, 1977 24 Broom NO, Thomson Fl: The influence of fixation conditions on the performance of glutaraldehyde-treated porcine aortic valves. Thorax (in press)