9. PARTIAL LEFT VENTRICULECTOMY Richard J. Kaplon and Patrick M. McCarthy Introduction End-stage heart failure currently afiFects 1 % of people under 55 years old, 9% of people over 80 years old, and is expected to continue to increase in prevalence.' Despite improvements in pharmacologic management of heart failure with newer agents such as angiotensin- converting enzyme inhibitors or beta-blockers such as carvedilol, approximately 25% of patients die while awaiting heart transplantation.^" "* Even with attempts at expanding the donor pool through "alternate recipient lists", the limited number of hearts available for transplantation has plateaued.*' * Ventricular-assist devices (VAD) have been effective as bridges to transplantation for those patients refractory to medical therapy, however, present use of VADs as destination therapy remains investigational.''' Clinical attempts at cardio- myoplasty and xenotransplantation have, thus far, been generally disappointing.'"'" Batista's Experience Based on his observations regarding the inter-relationship of heart mass and radius. Dr. Randas Batista developed the procedure he termed "partial left ventriculectomy" (PLV). In order to maintain a normal relationship, an increase in ventricular cavitary radius must lead to an increase in ventricular wall mass. When radius increases without an appropriate increase in mass, dilatation leads to clinical heart failure. According to the law of Laplace, intraventricular pressure is proportional to mural tension and inversely related to chamber radius. Batista reasoned that reducing the radius by excising part of the ventricular wall would diminish mural tension, improving overall left ventricular (LV) fiinction and decreasing myocardial oxygen consumption. Batista first presented this work as a case report of a 34 year-old patient with New Yoric Heart Association (NYHA) class IV heart failure who underwent PLV.'^ The patient's ejection Abaction (EF) rose from 17% pre-operatively to 44% at 2 months. Batista reported performing 154 similar such procedures during the following year; however, due to the socioeconomic circumstances of his practice, meaningfiil follow-up of these patients was unavailable. The primary etiologies of the end-stage heart failure for which Batista operated were Chagas', ischemic and dilated cardiomyopathies (CM). Roy Masters (editor), Surgical Options for the Treatment of Heart Failure, 157-164. © 1999 Kluwer Academic Publishers. Printedin the Netherlands. 158 R.J. Kaplan and P.M. McCarthy Batista brought his procedure to the United States, collaborating with Dr. Thomas Salerno. '^ At their combined institutions, they performed 120 PL Vs. The profiles for those patients being operated on in Brazil were the same as previously described, the pnmary mdication for surgery in Buffalo was dilated (viral or idiopathic) CM, with or without valvular uivolvement. Patients undergoing surgery in Buffalo included elderly patients or patients otherwise not transplant candidates. In the combined series from Buffalo and Brazil, patients underwent PLV alone (n=40), PLV plus valve replacement (n=51), PLV plus bypass (n=10), PLV plus autotransplantation (to reduce left atrial size to control alnal fibrillation; n=7), PLV plus others (n=12). In Brazil, most patients had an Alfieri mitral valve repair, whereas in Buffalo, most patients underwent mitral valve replacement with a tissue prosthesis.''' Patients in this group had a mean age of 53 years; 80% were male; all were in NYHA fiinctional class IV; all had EF's < 20%. From this experience, the 30 day mortality was 22% and 2 year mortality was approximately 45%. Ten percent of patients showed no improvement in NYHA functional class; however, 57% of survivors were in class 1 and 33% were in class II at follow-up. Again, complete follow-up of the Brazilian patients was not available. The Cleveland Clinic Experience Recognizing the potential benefit of Batista's procedure, we undertook a prospective study to critically evaluate the clinical benefits of ventricular volume reduction. Initially we chose only transplant candidates in NYHA fiinctional class III or IV despite maximal medical therapy, with an LV end-diastolic diameter (I.VEDD) greater than 7 cm on at least one recent echocardiogram. Choosing from primarily transplant candidates accomplished two goals: (a) patients not improved by the PLV could be relisted for transplantation and patients failing post-operatively could be bridged with a VAD; (b) transplant patients not undergoing PLV would serve as an appropriate control population compared to patients undergoing cardioreduction. After the excessive media reports surrounding the "Batista procedure", we received thousands of referrals for PLV; however, during the year that ensued we selected and performed 57 PLV's with mitral valve repair/replacement.'' Patients had a mean age of 53 years and 42 were male. Fifty-five patients were diagnosed pre-operatively with idiopathic dilated CM; one patient had valvular CM and one patient had familial CM. We chose to not include patients suffering ischemic CM or those with extensive myocardial scarring or fibrosis, believing that creating a smaller heart that remained scarred would not improve function. We perform a modification of the Dor aneurysmectomy for patients with ischemic cardiomyopathy, placing an endocardial patch to reduce ventncular volume.'* Fifty-four patients were awaiting transplantation, the remammg three were denied transplantation because of age or co-morbidities. Thirty-five patients were m NYHA class IV failure; the 21 patients in NYHA class III failure had an average of 2 hospital admissions for heart failure prior to surgery, and had previously been class IV. One patient was supported by the Heartmate LVAD (Thermocardiosystems, Inc., Wobum, MA) for 88 days but had developed a device infection requiring explantation. In addition to maximal medical therapy, 23 (40%) patients required inofropic support pre- operatively and 3 required intra-aortic balloon counterpulsation. Partial Left Ventriculectomy 159 Pre-operative echocardiography documented severe ventricular dysfunction (EF 14 4+/- 7.7%) and marked ventricular dilatation (L VEDD 8.4+/-1.1 cm; L V end-diastolic volume (LVEDV) 254+/-85ml) in all patients. Mitral regurgitataon (MR) was 2.8+ (range 0 to 4+) Even with 40% of patients on inotropic support, pre-PLV hemodynamics showed severe ventricular compromise (cardiac index (CI) 2.2+/-0.7 1/min/m^) with elevated filUng pressures (pulmonary artery pressures: 51+/-12 systolic, 36+/-8 mean, 27+/-8 diastolic mmHg; left atrial pressures: 24+/-8 mmHg). Peak oxygen consumption (MV02) was 10.6+/-3.9ml/kg/min. Our technique for PLV gradually evolved from Batista's initial method working with the heart beating and using the Alfieri mitral repair stitch.' We performed the operation using cardiopulmonary bypass with antegrade and retrograde cold blood cardioplegia. While we continued to use the Alfieri mitral repair in most cases, we incorporated the use of a posterior annuloplasty ring to support mitral leaflet approximation and reduce annulus size commensurate with ventricular reduction.'* We now routinely use a No 26 Cosgrove- Edwards ring (Baxter-Edwards, Irvine, CA) to undersize the dilated mitral annulus. The ventriculectomy resection comprises the lateral wall of the left ventricle in the circumflex coronary artery distribution (Figure 1). We begin our incision approximately 2 cm lateral to the left anterior descending coronary artery (l.AD) and 3 cm proximal to the apex. This is extended along the anterior papillary muscle to a point approximately 2 cm from the mitral annulus. Divided marginal branches of the circumflex coronary arterv' are oversewn Returning to the apex of the heart, the incision is extended to 3 cm parallel to the LAD and carried along the posterior papillary muscle to connect to the initial incision, thus creating an excised wedge of ventricle between the papillary muscles. The goal of the ventricular excision is to restore near-normal LVEDD This is determined bv the relation of the circumference of a circle to its diameter: evei-v 3.14 cm Figure 1. Partial left ventriculectomy. The lateral wall m the circimflex coronary artery distribution between the papillary muscles is excised (left). The ventriculotomy is closed between strips of felt or bovine pericardium (right). Reproduced with permission from McCarthy PM, Starhng RC. Wong et al Early results with partial left ventnculeclomy J Thorac Cardiovasc Surg 1997.U 4 756 160 RJ. Kaplon and P.M. McCarthy {K cm) of I.V wall resected (i.e. circumference) reduces LVEDD by 1 cm^ The limitation of the resection, therefore, is tlie papillaiy niuscles^ If intra-papillaiy LV wall resection was not adequate to reduce LVEDD to ncar-iionnal, papillary museles were resected, more ventricular wall excised, and the papillary heads reimplanted. Since the anterior wall and septum do most of the work post-operatively, wc prclcrentially resect the post,erior papillary muscle. With the ventricle open, the Alfien mitral valve repair is performed. The anterior and posterior mitral leaflets are approximated at the central portion of tlieir free edges with a single 4,0 Ethibond suture (Figure 2), The ventriculotomy is closed in three layers with strips of soft felt or bovine pericardium to distribute tension evenly along the suture line (Figure 1). After the cross clamp is removed, tricuspid valve repair can be perfonned as needed. All patients were evaluated intraoperatively with transesophageal echocai-diography. Fiftj'-five patients undcirivcnt concomitant Alfieri mitral valve repair, 51 with ring amiulo- plasty; two patients required mitral valve replacement for intnnsic mitral leaflet patliolog>'. A De Vega tricuspid annuloplasty was performed in 33 (58%) patients and one patient required a Cosgrove-Edwai'ds ring for 4+ tricuspid regurgitation. Five patients required coronarj' aiter>' b\'pass grafting, one required aortic valve repair and one needed aortic valve replacement. Eleven patients required LVAD placement perioperatively for low cardiac output. The technique for LVAD insertion was similar to our previous reports. • Hpire 2, Partial left I'entriciilecloiny, llic free edges ofthe mitral leaflets are approximated with a 4.0 suture (Alfieri repair). Reproduced aith permission rrom McCarthy VM, Starlmg RC, Wong et at Early resulte with partial left ventnculectomy. I Thorac Cactliovasc Surg 1997:1 i4;75fi Partial Left Ventnculectomy 161 Because of reports of high risk of sudden death due to arrhythmias, all patients were maintained on amiodarone post-operatively.'^ Further, because we have seen a high incidence of left atrial thrombus, all patients are now placed on warfarin sodium (Coumadin). Post-operatively, six patients required relisting for transplantation. Five have been transplanted and one is still waiting. Of the eleven patients requiring L,VAD placement, two died, six were transplanted and two are still waiting. One patient improved and the L,VAJ^ was explanted. There were two early and seven late deaths. Both early deaths occurred in patients supported on L VADs. Three patients died suddenly between three and nine months post-operatively. These were likely due to arrhythmias, despite amiodarone therapy. Three late deaths were due to progression of heart failure and one was due to right ventricular failure after transplantation. Hospital mortality was 3.5% and one year actuarial survi\'al was82.1+/-5.5%. At 3 month follow-up, most patients were symptomatically improved (Table 1). The NYHA class, EF, LVEDD, LVEDV, MR and MV02 were all significantly better, only cardiac index did not change In total, 24 patients were considered "failures" of therapy: 11 required LVAID placement, 6 required relisting for transplantation, and seven non-LVAJ) patients died The only factor that was associated with failure was age < 40 years, however, more detailed analysis of this subgroup revealed only that this appeared to be a sicker group of patients preoperatively." As compared to patients older than 40, the younger group had more UNOS status 1 patients (81.8% vs. 30.4%), more patients in NYHA class IV failure (90% vs. 56.5%) and had a greater pre-operative inotrope requirement (72.7%) vs. 32.6%)). Age itself did not appear to be a factor. Table 1. Cleveland Clinic Experience. Pre-operative and 3 month results. Parameter NYHA Class EF LVEDV LVEDD MR MV02 CI Pre-operative (mean ± SDj 3.7 14.4±7.7% 254±85 ml 8.4±L1 cm 2.8±1.1 10.6±3.9ml/kg/min 2.2 ±0.7 1/min/m' Post-operative 3 months (mean ± SDj 2.2 23.2±10.7% 179±73 ml 6.3 ±0.9 cm 0.65±0.8 15.3±4.5ml/k.g/min 2.2 1/min/m' "p" value .001 .001 .001 .001 .001 NYHA, New York Heart Association EF, Ejection Fraction LVEDV, Left Ventricular End Diastolic Volume, LVDD, Left Ventricular End Diastolic Dimension MR, Milrai Regurgitation MV02, Peak Oxygen Consumption, CI, Cardiac Index 162 R.J. Kaplon and P.M. McCarthy Discussion These early results from our experience are encouraging. Our one-year actuarial survival of 82% compares favorably with 79% one-year actuarial survival for all heart transplants reported in the International Society of Heart and Lung Transplantation 1997 registry' report.'' Similarly, other centres have begun to report favorable outcomes with PLV Angelini, et al., report their experience with 14 patients undergoing PLV."' Unlike the patients treated at the Cleveland Clinic, their population was older (mean age 65 years), more heterogeneous in terms of etiology of CM (eight idiopathic, 5 ischemic, one valvular), and 13 were not considered transplant candidates. Nonetheless, they report an in-hospital sunival of 78%), and only one late death, likely due to an arrhythmia. Patients in this senes experienced a significant increase in CI from 1.9 1/min to 2 7 1/min. The mechanism by which PLV benefits patients remain controversial In comparison to Batista's, Salerno's and Angelini's experience, our patients did not demonstrate a major improvement in CI. Nonetheless, in all series, survival was better than the expected one- year survival of similar patients otherwise managed medically,'' In a multiple compartment elastance model attempting to stimulate PLV, Dickstein, et al., found that diastolic changes offset improvement in systolic fiinction.^^ They believe that, according to the Frank-StarUng relationship, overall pump ftinction is, at least short-term, depressed after PLV. Their argument, however, is based on excision of ventricular mass. As Chanda, et al., point out, the goal of the Batista operation is to reduce venfriculai- volume, not mass.'"* Since ventricular mass does not increase proportionally with chamber dilatation, volume reduction surgery should decrease wall stress and improve overall caidiac ftinction. Another area of confroversy regarding the mechanism of improvement seen with PLV is the role of mifral valve reconstruction in these patients. Boiling, et al., demonstrate that mitral repair in patients with severe ventricular ftinction and 4+ MR can be performed with reasonable survival and good ventricular functional improvement.^'' They performed ring- annuloplasty mitral repair in 48 patients, all of whom had pre-operative 4+ MR, were receiving maximal medical therapy and were in either NYHA class III or IV failure. In their study, one and two year actuarial survivals were 82%) and 71 %, respectively EF improved from 17+/-3%) to 26+/-8%o, and NYHA functional class was reduced from 3.9+/-0,3 to 2.0+/-0.6. In comparison to patients undergoing PLV, however. Boiling notes that his patients have more severe MR (4+ vs 2.8+ in our experience), better ventricular function, smaller L V size and less inofropic requirement. While Boiling's work offers one possible mechanism of improvement seen with PLV, fiirther study is required to better understand the effect of volume reduction on the left ventricle. Conclusion Hven with these early successes with PLV, caution must be exercised with regard to the future of this procedure, as stated in the Society of Thoracic Surgeons position paper '^ Experience with this operation is limited, with only short-term results published m peer- review journals. Patient selection, a factor that we consider critical to outcome, has varied Partial Left Ventriculectomy 163 among institutions. While some groups have chosen to perform PLV on non-transplant patients, we believe that failures of PLV should be transplant or LVAD candidates. Other institutions have elected to include ischemic CM as an indication for PLV; we prefer to perform a modified Dor procedure for this entity. Our early clinical impression is that routine use of Dobutamine echocardiography, PET scans and cardiac MRI will help to determine which patients will most benefit from cardioreduction. We believe that the ftiture of this operation will rest with objective scientific scrutiny, performed by multidisciplinaiy teams, at centres dedicated to the management and care of heart-failure patients. 164 R.J. Kaplan and P.M. McCarlhy References 1. O'Connell JB, Bristow MR. Economic impact of heart failure in the United States: time for a different approach J Heart Lung Transplant I994;13:S107-12. 2. Clark AL, Coats .\J. New evidence for improved survival in chronic heart failure. Clin Cardiol 1994,l7(2):55-8. .1 Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349-55. 4. Saxon LA. Stevenson WG, Fonarow G, et al. Predicting death from progressive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol l993;72(l):62-5. 5. L^s H, Scholl FG, Drinkwater DC, et al. The alternate recipient list for heart transplantation: Does it work? J Heart Lung Tran-splant 1997;16:735-42. 6. Hosenpud JD, Bennett LE, Berkeley KM, Fiol B, Novick RJ. The registry of the International Society tor Heart and Lung Transplantation: Fourteenth official report - 1997. J Heart l^ung Transplant 1997;16:691-712, 7. Frazier OH. First use of an untethered, vented electric left ventricular assist device for long-term support. Circulation 1994;2908-14. 8 Portner PM,. Oyer PE, Pennington DG, etal. Implantable left ventricular a.ssist system: bridge to transplantation and the future .Ann Thorac Surg 1989;47:142-50. 9 McCarthy PM, Young JB, Smedira NG, Hobbs RF^, Vargo RL, Starling RC. Permanent mechanical circulator,' support with an implantable left ventricular assist device. Ann Thorac Surg 1997;63:1458- 61. 10. Chiu RC-J Cardiomyoplasty. In: I'dmunds LH, editor. Cardiac surgery in the adult New York: McGTaw-Hill;1997: 1491-504. 11 Lin SS, Piatt JL Immunologic barriers to xenotransplantation. J He:u1 Lung Transplant 1996:15:547- 55. 12 Batista RJV, Santos JLV. Takeshita N, Bocchino L, Lima PN. Cunha MA. Partial left ventriculectomy to improve left ventricular fiinction in end-stage heart disease. J Card Surg I996;l 1:96-7. 13 Batista RJV, Verde J, Nery P. et al. Partialleftventriculectomytotreatend-stageheartdisea.se .'\nn lliorac Surg 1997;64:634-8. 14 Fucci C. Sandrelli L, Pardini A. Torracca L, Ferrari M, Alfieri O. Improved results with mitral valve repair using new surgical techniques. Eur J Cardiolhorac Surg I995;9:621-7. 15. McCarthy JF. McCarthy PM, Starling RC, et al. Partial left ventriculec-tomy and mitral valve repair for end-stage congestive heart failure. Eur J Cardiothorac Surg I998;in press. 16 Dor V. Left ventricular aneurysms: the endoventricular circular patch plasty. Sem Thorac Cardiovasc Surg 1997;9{2): 123-30. 17. McCarthy PM, Starling RC, Wong J, et al. Early results with partial left ventriculectomy. J Thorac Cardiovasc Surg 1997;! 14:755-65. 18 Cosgrove DM, Xrcidi J, Rodriguez L, Stewart WJ, Powell K. Thomas JD. Initial experience with the Cosgrove-Edwards annuloplasty system. Ann Thorac Surg 1995;60:449-504. 19 McCarthy PM, Wang N, Vargo RL. Preperitoneal insertion of the Heartmate 1000 IP implantable left ventricular device. Ann Thorac Surg 1994;57:634-8.20. 20 .\ngelini GD. Pryn S, Mehta D et al. Left ventricular volume reduc-tion for end-stage heart failure. 1 Jincet 1997;350:489. 21 Cowie MR, Mosterd /V Wood D/\. et al. The epidemiology of heart failure. Eur Heart J 1997:18:208- 25. 22 Dickstein ML, Spotnitz HM, Rose EA, Burkhoff D. Heart reduction surgery: An analysis of the impact on cardiac function J Thorac Cardiovasc Surg 1997;113:1032-40. 23 Chanda J, Kuribayashi R. Abe T. Batista operation for dilated cardiomyopathy: A physiologic concept. J Thorac Cardiovasc Surg 1998;! 15:261. 24 Boiling SF, Pagani FD, Deeb GM, Bach DS. Intermediate-term outcome of mitral reconstruction in cardiomyopathy. J Thorac Cardiovasc Surg; 115:381-8. 25 Replogle RL, Kaiser GC. Cohn LH, et al Left ventricular reduction surgery. Ann Thorac Surg 1997;63:909-10. 10. XENOTRANSPLANTATION Farah N.K. Bhatti and John Wallwork Introduction While transplantation is an established form of treatment for many end stage disease processes that lead to heart failure, the number of tiansplants performed is limited by a relative lack of donor organs. This has led not only to a levelling off in heart transplant activity world-wide, but actually to a decrease in the number of operations perlbrmed in 1995 and 1996, despite the use of older organ donors each year. Although waiting lists are kept artificially low by patient selection, the disparity between growing waiting lists and falling transplant numbers continues to widen leading to a proportion of people dying whilst awaiting trans-plant. In the United Kingdom in 1996, of people waiting for a heart, only 63% were transplanted, and 14% died while waiting.' Figures from the United Network for Organ Sharing (UNOS) at the end of 1996 show a similar situation, with 3700 people waiting for a heart transplant in the U.S.A., 2343 transplants being performed, and 744 deaths on the waiting list. The mismatch between the waiting lists and transplants actually performed is depicted, for all organs, in Figure 1. Potential Solution to Donor Shortage A number of approaches can be applied to try and resolve this issue Firstly, optimal utilization must be made of those organs that are available and this includes strategies such as multiorgan donation and coordination of transplant services to minimize organ wastage Secondly, the development of artificial organs and tissues that could be implanted permanently would alleviate the need for human donor organs. There are a number of left ventricular assist devices available and these have been used as both to allow rccover\' of the heart as well as a bridge to transplantation (the latter use, of course, delays but does not prevent the need for a donor heart). Total artificial hearts are also a focus of active research; whilst theoretical benefits include helping the organ shortage situation and the avoidance of long term immunosuppressive therapy, problems such as haemolysis, thromboembolism, line infection and developing portable power sources all need addressing. Finally, xenotransplantion, the transplantation of organs between different species, could provide a solution to the problem. The main advantage of xenotransplantation would be the provision of a readily available supply of organs to meet the demand, and perhaps being Roy Masters (editor). Surgical Options for the Treatment of Heart Failure. 165-173. © 1999 Kluwer Academic Publishers. Printed in the Netherlands. 166 F. N.K. Bhatti and J. Wallwork 60000 Waiting List Transplants Performed 1990 1992 1994 1996 Year Figure 1 Numbers of Patients on Waiting Lists for Transplantation & Number ofTransptants Performed: USA Data is shown for all organs m the United States. The increasing disparity between the steadily growing waiting list and the relatively static number of transplants performed can be seen. able to widen the eligibility criteria to join the transplant waiting list. Additional benefits would include practical considerations such as performing planned procedures with shorter ischaemic times. Historical Overview of Cardiac Xenotransplantation There are 8 aca)unts in the literature of humans receiving xenogeneic hearts.^ From the first documented attempt at cardiac xenotransplantation by Hardy in 1964 to the last case of Baby Fac performed by Bailey at Loma Linda in 1984, none has been particularly successful In five of the cases, non-human pnmate donors were used (chimpanzees and baboons) in either an orthotopic or heterotopic position; all failed either due to an inability to support the circulation or due to vascular rejection, although one patient did survive out to 20 days before death occurred. In three reports, all in 1968. sheep and pig hearts were used; none of these organs survived beyond a few minutes. The world experience is summarised in Table 1 ' [...]... Nature Med 199 7 Mar; 3(3): 28 2-6 Smith JA, Boyd KM, Eds Lives in the Balance The Ethics of using animals in biomedical research The Report of a Working Party of the Institute of Medical Ethics OUP 199 1 Report on The Ethics of Xenotransplantation The Nuffield Council of Bioethics March 199 6 Report by The Advisory Group on the Ethics of Xenotransplantation Chaired by Profes.sor Ian Kennedy January 199 7 11... widely practiced therapy for heart failure patients While Roy Masters (editor) Surgical Options for the Treatment of Heart Failure 17 5-1 86 (e> 199 9 Kluwer Academic Publishers Printed in the Netherlands 176 T Mussivand, PJ Hendry, R.G Masters, and WJ, Keon Cuniestlwe: Heart Failure Estimated Patient Population -1 91 7 15,000,000] Canada World Congestlwe Heart Failure Annual Deaths - 1S97 TTSSKJI scondaf}/... The estimated patient population and number of deaths related to congcsti\'c heart failure for the U.S.A., Canada and the World are shown in Figure 1J In the U.S.A., heart failure is the primary diagnosis of over 90 0,000 hospitalizations per year with an annual new diagnosis of over 400,000 individuals.*'' The estimated cost of heart failure in the U.S.A for 199 8 exceeded $20 Billion.'" Even with the. .. rtificial Hearts Total Artificial Hearts (TAHs) are designed to replace the total heart (both ventricles) and require excision of the native heart for placement of the device At last report, 9 different total artificial hearts had been clinically utilized in 323 patients, between 196 9- 1 99 7 (Table I).''' The vast majority (> 85%) of these implants were performed with Jarvik total artificial heart devices... and decay accelerating factor Tran.sactions of the Associations of American Physicians CIV, 199 1; 16 4-7 2 Cozzi E, White DJG The generation of transgenic pigs as potential organ donors for humans Nature Med 199 5; 1 (9) : 96 4-6 Langford GA, Yannoutsos E, Cozzi E et al Production of pigs transgenic for human decay accelerating factor Trans Proc 199 4; 26(3): 140 0-1 Schmoeckel M, NoUert G, Shahmohammadi M... a concordant species Heart Lung Transplant 199 7 Jul;16(7):75 8-6 4 Hasan RI, et al Prolonged survival of hamster to rat heart xenografts with cyclophosphamide therapy Tramplant Proc 199 2 Apr; 24(2): 51 7-8 Waterworth PD Cozzi E, Tolan MJ et al Pig to primate cardiac xenotransplantation and cyclophosphamide therapy Trans Proel 997 ; 29: 89 9- 9 00 Stark JH Smit JA Gridelli B Sensitivity of baboon lymphocytes... aintrol pig hearts and had a cardiac performance similar to the Xenotransplantation 1 69 rhesus hearts'' Furthermore, markers of myocardial damage, such as creatme phosphokinase remained low in the hDAF transgenic pig hearts and the rhesus hearts while rising significantly in the control pig hearts: Only the non-transgenic pig hearts showed any evidence of HAR histologically In Vivo Cardiac Studies The next... circulate in an inactive form Activation of the system, either by the classical (antigen-antibody mediated) or the alternative pathway, leads to the generation of C3b by C3 convertase and then membrane attack complex (MAC) There exist, however, a number of molecules that serve to prevent self-damage on activation of the complement system; these molecules are termed regulators of complement activity (RCAs)... resistance of alloactivated cells to CyA Transplant Int 199 4; 7: 37 2-8 Schmoeckel M Bhatti FNK, Zaidi A et al Orthotopic heart transplantation in a transgenic pig to primate model Transplantation 199 8; 65(12): 157 0-7 Morris RE Mechanisms of action of new immunosuppressive drugs Therapeutic Drug Monitoring 199 5; 17(6):56 4 -9 Patience C Takeuchi Y, Weiss RA Infection of human cells by an endogenous retrovirus of. .. being utilized for extended durations outside of the hospital setting, systems are being developed utilizing advanced technologies which will allow for longer term out of hospital, circulatory support."'' Heart Failure Circulatory insufficiency caused by the inability of the heart to pump blood to the organs m sulTicient amounts to meet the requirements is defmed as congestive heart failure (otherwise referred . report - 199 7. J Heart l^ung Transplant 199 7;16: 69 1-7 12, 7. Frazier OH. First use of an untethered, vented electric left ventricular assist device for long-term support. Circulation 199 4; 290 8-1 4 ventricular volume reduc-tion for end-stage heart failure. 1 Jincet 199 7;350:4 89. 21 Cowie MR, Mosterd /V Wood D/. et al. The epidemiology of heart failure. Eur Heart J 199 7:18:20 8- 25. 22 Dickstein. supply of organs to meet the demand, and perhaps being Roy Masters (editor). Surgical Options for the Treatment of Heart Failure. 16 5-1 73. © 199 9 Kluwer Academic Publishers. Printed in the