LASKER CLINICAL MEDICAL RESEARCH AWARD COMMENTARY

The surprising rise of nonthrombogenic valvular surgery

Alain Carpentier

Surgery has always been regarded as an art rather than a science—the art of curing dis- eases by manipulating instruments with one’s hands. In the past, progress resulted from the development of new ways of cutting, excising, resealing and suturing. Nowadays, this is no longer the case. My own specialty——did not exist 60 years ago. Its spectacular devel- opment would not have been possible with- out the contribution of basic sciences and engineering. Surgeons who participated in its development had to master these sciences. A visit to a cardiac surgery operating room may give an idea of the influence of these dis- ciplines. In a 50-square-meter room, a patient is lying on the operating table with his chest open and his beating heart exposed to the dazzling light of three “suns of crystal”, as Figure 1 First (homemade) glutaraldehyde-treated pig valve implanted in human. Left, Teflon-covered Paul Valery named the operating lights hang- stainless steel stent used to support the valve, preventing its deformation during implantation. Right, ing from the ceiling. Around the table, ten stent covered with Dacron fabric to facilitate fixation and host-tissue incorporation. The porcine valve phantom-like people, dressed from head to has been sutured into the stent preserving a full motion of the leaflets, avoiding fibrous incorporation. feet in blue gowns, bustle about, exchanging From ref. 6. few words. The patient’s life hangs on sophis- ticated machinery. Multiple tubes, wires, makers, defibrillators or cardiac-valve pros- that her life could be saved by oxygenating catheters connect him to monitoring devices, theses of different types are also available. her blood if he had some sort of heart-lung automated drug-delivery pumps, a respira- So today, chemistry, physics, electronics and machine. Educating himself in bioengineer- tor and a heart-lung machine that provides engineering do more for the success of a sur- ing, he spent ten years with the help of his adequate oxygenation and perfusion to the gical operation than surgery itself. wife Mary to build the first prototype, and an organs during the open heart procedure. The purpose of this brief description of additional ten years before he could carry out In an adjacent room, laser systems, exter- my daily environment is to recognize the the world’s first open-heart procedure under nal defibrillators, counter pulsation pumps, contribution of the sciences to surgery and extracorporeal circulation1. This seminal con- ventricular-assist devices and computer- to pay tribute to all the dedicated specialists, tribution opened a new therapeutic avenue: assisted instruments are ready to be used if technicians and nurses who participate in this open-heart surgery, which saves over one mil- necessary. Implantable devices such as pace- endeavor. lion lives every year. Progress in medicine is often triggered by My own contributions followed a similar Alain Carpentier is professor emeritus at the emotional circumstances concerning a par- pattern. As a young resident of cardiac sur- University of V René Descartes and cardiac ticular patient. John Gibbon’s invention of gery in the early 1960s at Hôpital Broussais surgeon at Assistance Publique–Hôpitaux de Paris, the heart-lung machine was triggered by the in Paris, I had been struck by an artist with Hôpital Européen Georges Pompidou, 20 rue observation of a young woman he took care a valvular disease. His life had been saved by Leblanc, 75015 Paris, France. of as a resident in surgery in the early 1930s. the implantation of a valvular prosthesis, but Published online 17 September 2007; doi:10.1038/ As she was dying from a massive pulmonary three months later he presented with a cere- nm1645 embolism despite his efforts, he thought bral embolism. A clot had formed at the site

NATURE MEDICINE VOLUME 13 | NUMBER 10 | OCTOBER 2007 xvii COMMENTARY a Figure 2 First- and second-generation 100 bioprostheses. (a) Primary-failure curves of the first-generation bioprostheses. Failures began >Age 60 to occur 6–7 years after operation. Beyond seven years, the bioprostheses deteriorate 80 es (%) further at different speed depending on the

alv Age 35–60 patients’ age, indicated in years next to each curve. Data from ref. 8. The cause of failure was not immunological response or collagen 60 degeneration but, unexpectedly, calcification,

µ these improvements, their durability markedly ( 100 increased—90% of patients over 60 years of age Ca do not require a second surgery 20 years after the 50 first operation. n = 31 Porcine Pericardial 0 Glutaraldehyde Glutaraldehyde plus surfactant of the valve and migrated to the brain, caus- grafts. In 1964, the first mechanical valve a lesser risk of clot formation3. As a young ing serious damage. The same valve that saved prosthesis, developed by Albert Starr and resident, I was asked to collect homograft the patient had now affected the quality of Lowell Edwards, had been in use for only four valves from cadavers by my mentor, Jean his life to a point in which he could not paint years2. The lives of hundreds of patients had Paul Binet, but I was soon confronted with a anymore. At that very moment, I decided to been saved by this remarkable invention. But French law that did not permit tissue collec- devote my research to the challenge of valve the risk of clot formation and the need for tion during the first 48 hours after death, to thrombogenicity. long-term anticoagulation to minimize that allow the family to oppose tissue harvest. As I can identify four periods in this research, risk were severe limitations, particularly in a consequence, most of the retrieved valves which has spanned over 40 years from 1964 children and for women of childbearing age. were infected and not suitable for use. This to the present time. The first period encom- In London, Donald Ross had shown that drawback stimulated me to revive the idea passed my attempts to develop valvular xeno- valves retrieved from human cadavers carried of using pig valves, which had been tried

Aorta

Inflated balloon Mitral valve deploying valve in stent Valve within stent Native aortic valve orifice

Apex of left ventricle

Figure 3 A bioprosthesis compressed within a stent can be introduced percutaneously or through the apex of the beating heart. Once in the proper position, the bioprosthesis is deployed by balloon dilation and automatically secured into position by hooks penetrating the native aortic valve orifice; the diseased aortic valve is laminated by the dilated stent.

xviii VOLUME 13 | NUMBER 10 | OCTOBER 2007 NATURE MEDICINE COMMENTARY experimentally in Oxford by Carlos Duran. Anterior The challenge remaining was the immuno- a leaflet logical response: porcine valves implanted in sheep were rejected in a few weeks. The residency period is important in the Regurgitant education of a surgeon because it gives access orifice to various disciplines. During my rotation in orthopedic surgery, I had the opportunity to Posterior Annulus Remodeling annuloplasty ring assist Robert Judet, the inventor of the arti- leaflet restores normal geometry ficial hip. He used human skin to cover the and leaflet coaptation cartilage of knees affected by arthritis. As the b skin is highly antigenic, I was surprised to see little inflammatory reaction in these patients. I inferred that the mercury-based solution that was only intended to sterilize the skin before implantation had also the ability to minimize immunological reactions, most probably by killing cells and modifying some of the anti- genic components. This observation led me to treat the pig valves with a similar solution before their Asymmetrical annular Ring secured to the dilatation annulus by sutures implantation in sheep. The results looked Anterior leaflet of promising: not only did these valves retain mitral valve their function, but they also did not trigger any clot formation, owing to their normal hemodynamic response and high biocompat- Ring ibility. In 1965, because of the pressing need Regurgitant valve Competent valve for nonthrombogenic valves, Jean-Paul Binet and I began to implant mercury salt–treated porcine valves in patients in whom anticoagu- Left ventricle Myocardial infarction lation was contraindicated4. Our excellent early results were marred by two complications in some patients after one or two years: inflammatory reactions Figure 4 Valve reconstruction. (a) Surgeon’s view of the diseased mitral valve before (left) and after and collagen denaturation. The long-stand- (right) correction by a remodeling annuloplasty using suitably shaped and sized prosthetic rings. The ing hypothesis of tissue graft regeneration regurgitant mitral valve shows a severe deformation of the annulus fibrosus, which attaches the two 5 propounded by Nageotte and Bert was not leaflets (left). A ring secured to the annulus remodels and stabilizes it, effectively restoring leaflet confirmed by the facts. I wrote: “The theo- coaptation and solving the regurgitation (right). (b) Top, an example of ring implantation for mitral valve retical possibility of graft regeneration by regurgitation due to myocardial infarction (asymmetric annulus). Bottom, hearts cut longitudinally show host fibroblast ingrowth failed to materialize. (left) the regurgitant mitral valve with regurgitant blood flow (arrow) and (right) the corrected mitral Cellular infiltration proved to be more harm- valve with blood flow now directed toward the aorta (arrow). ful than beneficial, as the cells invading the grafted tissue were most often inflammatory fixation, led to the discovery in 1968 of the tation (Fig. 1). Clearly, the term ‘graft’ was no in nature. A method of tissue conditioning dual effect of glutaraldehyde on pig valves: it longer appropriate to define this new type should be developed which would prevent prevented collagen denaturation by intermo- of biological material. I proposed the term inflammatory reactions and collagen denatur- lecular cross linkages, and it reduced immu- ‘bioprosthesis’, which indicates the biological ation”6. These new challenges required much nological responses. Its two terminal aldehyde origin and the prosthetic fate of these valves. more expertise in chemistry and immunology groups and its five-carbon chain established The results of these research studies and the than what I had acquired during my medical covalent binding and cross-linkages with the early clinical experience became public in the education. collagen molecules. In addition, glutaralde- medical literature in 1969: “As opposed to a The second period of my research led to the hyde reduced the immunological response by graft, the durability of which depends upon development of the concept of the biopros- cell fixation and by ‘masking’ the host anti- cell viability or tissue regeneration, the dura- thesis. Although I was already an active car- genic determinants. It was interesting to note bility of a bioprosthetic tissue relies on the diac surgeon in the service of Charles Dubost that neither the four-carbon chain nor the unfailing stability of the chemically treated at Hôpital Broussais, I persuaded him (with six-carbon chain dialdehydes worked. Most biological material and the prevention of host some difficulty) to let me spend two days a important was the fact that, similarly to that cell ingrowth”7. week at the Faculty of Sciences. This comple- treated with mercury salts, glutaraldehyde- As I did not apply for a patent, several mentary training and the development of my treated tissue retained its nonthrombogenic medical industries could manufacture the own research laboratory, which allowed me nature. bioprostheses without limitation. Edwards to work during the evenings and to explore We mounted glutaraldehyde-treated pig Laboratories were the first to do so, owing all the existing chemical methods of tissue valves into a stent to facilitate surgical implan- to Albert Starr, who introduced me to the

NATURE MEDICINE VOLUME 13 | NUMBER 10 | OCTOBER 2007 xix COMMENTARY company—showing remarkable generosity, as research comes from other people’s discover- be reconstructed, rather than replaced with this new valve could challenge his own pros- ies.” I have always thought that the best way a bioprosthesis or a mechanical valve13. For thesis. Indeed, over the next six years, valvu- to avoid disappointment is to challenge my the first time in the history of valvular dis- lar bioprostheses were used more and more own contributions. While I was developing eases, patients could be cured for the rest of in clinical practice. Observations in some the valvular bioprostheses, I was also trying their lives. patients during this six-year period showed to reduce the need to use them by develop- that collagen denaturation and immuno- ing techniques to preserve the patient’s own ACKNOWLEDGMENTS I would like to acknowledge my second family: the logical response had been almost completely valve. members of my research laboratory. As Diaghilev eliminated. However, an unexpected compli- In my early days as cardiac surgeon, I was said to Nijinsky, I often tell them, “Surprise me!”, and cation emerged in patients younger than 60 struck by the fact that some retrieved valves, they do it. I am proud to mention among others the years of age: tissue calcification, which altered although severely regurgitant, had still a rea- seminal contributions of J.C. Chachques to dynamic 8 , P. Menasché to cell therapy, N. Lila long-term valve function (Fig. 2a) . sonably good configuration. Valve-repair to the study of HLA-G histocompatibility antigen The new challenge of tissue calcification techniques had been tried at the beginning expression in transplanted patients, and E. Martinod, opened the third period of my research. I of open-heart surgery, but had been aban- who first showed the surprising metaplasia of an returned to the lab and, with the help of my doned because the results were unpredictable. aorta into a true neo-trachea when implanted into the wife, Sophie, tried to improve the method of Having the opportunity to carefully analyze tracheal environment. My final words are to express my deep gratitude to the Lasker Foundation for the glutaraldehyde fixation by adding calcium- these techniques during surgery, I found a honor of being distinguished with such a highly mitigating adjuncts9. At the same time, I common downside to them: they were only prestigious award that I share with all the members of improved the valve design to minimize flow palliative. They corrected valve regurgitation my laboratory and my department of cardiac surgery. turbulence, an additional cause of calcifica- by narrowing the fibrous annulus to which the 1. Gibbon, J.H. Jr. Application of a mechanical heart tion (Fig. 2b). These improvements led to a leaflets were attached; that is, by producing a and lung apparatus to cardiac surgery. Minn. Med. 37, near doubling of the average durability of the certain degree of valve stenosis. They did not 171–185 (1954). 2. Starr, A. & Edwards, M.L. Mitral replacement: clinical bioprostheses and to extension of their indi- restore the shape of the mitral valve orifice, experience with a ball-valve prosthesis. Ann. Surg. 154, cation to younger patients. Valve calcification nor a normal leaflet motion, nor a large and 726–740 (1961). remains a challenge, however, in very young harmonious surface of coaptation between 3. Ross, D.N. Homograft replacement of the aortic valve. Lancet 2, 487 (1962). patients and children. This last challenge leaflets. This problem occupied my mind for 4. Binet, J.P., Carpentier, A., Langlois, J., Duran, C. & occupies our current research, with promis- several months. Colvez, P. Implantation de valves hétérogènes dans ing, new glutaraldehyde-based processes10. One November evening in 1967, as I left le traitement de cardiopathies aortiques. C. R. Acad. Sci. Hebd. Seances Acad. Sci. D 261, 5733–5734 Although the durability of valvular biopros- Hôpital Broussais, I passed under the stone (1965). theses is limited, the number of bioprosthe- arch framing the iron gates and was struck 5. Nageotte, J. Sur la greffe des tissus morts. C. R. Soc. Biol. (Paris) 1, 925–933 (1917). ses implanted worldwide increases by three to by its similarity to the structure of the mitral 6. Carpentier, A. et al. Mitral and tricuspid valve replace- five percent every year because of the superior valve. If the arch were partially destroyed, a ment with frame-mounted aortic heterografts. J. Thorac. quality of life provided by nonthrombogenic good architect would restore its geometry Cardiovasc. Surg. 56, 388–394 (1968). 7. Carpentier, A., Lemaigre, G., Robert, L., Carpentier, valves. In the near future, the use of biopros- using a support structure of appropriate size S. & Dubost, C. Biological factors affecting long-term thesis will allow surgeons to implant valves and shape, which would fit with the geom- results of valvular heterografts. J. Thorac. Cardiovasc. Surg. 58, 467–483 (1969). without extracorporeal circulation using etry of the gates. Clearly, a surgeon should do 8. Magilligan, D.J. Jr., Lewis, J.W. Jr., Tilley, B. & Peterson, noninvasive techniques through the apex of the same for the mitral valve! The concept of E. The porcine bioprosthetic valve. Twelve years later. the heart (Fig. 3) or by simple catheterization annular remodeling using a prosthetic ring J. Thorac. Cardiovasc. Surg. 89, 499–507 (1985). 11 9. Carpentier, A., Nashef, A., Carpentier, S., Ahmed, A. & through the skin , techniques that would (Fig. 4a) emerged from this vision. This device Goussef, N. Techniques for prevention of calcification not be possible with the current mechanical reshapes and stabilizes the structure that holds of valvular bioprostheses. Circulation 70, I165–I168 (1984). valves. the valve, therefore restoring normal function. 10. Carpentier, S.M. et al. Heat treatment mitigates calci- It is not surprising that patients choose As the ring is readily covered by host tissue fication of valvular bioprostheses. Ann. Thorac. Surg. valvular bioprosthesis for a better quality of and the patient keeps the original valve, anti- 66, S264–S266 (1998). 11. Khambadkone, S. et al. Percutaneous pulmonary valve life. What surprises me is that, after almost 30 coagulation treatment is not necessary. implantation in humans: results in 59 consecutive years, glutaraldehyde remains as the unsur- The introduction of remodeling annulo- patients. Circulation 112, 1189–1197 (2005). 12. Carpentier, A. Cardiac valve surgery—the “French passed element in animal-tissue processing. plasty allowed the development of comple- Correction”. J. Thorac. Cardiovasc. Surg. 86, 323–337 The fourth chapter in my research—valve mentary techniques of valve reconstruction (1983). reconstruction—has unfolded in parallel to (Fig. 4b)12. This so-called ‘French correc- 13. Braunberger, E. et al. Very long-term results (more than 20 years) of valve repair with Carpentier’s techniques the first three. The Nobel Laureate André tion’, with a proven durability of up to 25 in nonrheumatic mitral valve insufficiency. Circulation Lwoff used to say, “Disappointment in years, allows 50–90% of diseased valves to 104, I8–I11 (2001).

xx VOLUME 13 | NUMBER 10 | OCTOBER 2007 NATURE MEDICINE