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Eur J Cardiothorac Surg 2004;26:S48-S53
© 2004 Elsevier Science NL
Review |
Académie Nationale de Médecine, Paris, France
* Address: Service de Chirurgie Thoracique et Cardiovasculaire, Hôpital Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil Cedex, France. Tel.: +33 1 49 81 25 51; fax: +33 1 49 81 25 52. (Email: daniel.loisance{at}wanadoo.fr).
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Abstract |
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 Top Abstract 1. Introduction2. The systems presently...3. The clinical experience4. The futureAppendixReferences |
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Key Words: Cardiac failure • Cardiac transplantation • Artificial heart • Mechanical circulatory support
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1. Introduction |
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TopAbstract1. Introduction2. The systems presently...3. The clinical experience4. The futureAppendixReferences |
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In about the same time frame, various devices have been introduced in the clinical practice, which permit, in patients about to die, to wait safely and comfortably for a cardiac transplantation or the recovery of the native cardiac function. Some systems have even been shown to improve the chances of a patient with chronic cardiac insufficiency to survive longer and better than the patients maintained on medical therapy alone.
A novel therapy for cardiac failure in every presentation either acute or chronic actually based on the use of artificial ventricles remains necessary. The incidence of congestive heart failure is growing as a consequence of progress in the medical and surgical treatment of heart disease, and the current prevalence in France, 225 cases per million, in the age range of 61–70 years, is growing every year. The surgical techniques presently available are not meeting the actual need. The failure of cardiac transplantation to meet the real demand is now obvious: shortage of donors is a reality and no one knows how to solve this major societal issue. Problems related to immuno-suppression and the associated risks further compromise the chances of transplantation becoming the final answer. There are also real limitations to the most advanced medical methods (the tailored optimal triple therapy, possibly associated with sophisticated methods such as ventricular resynchronisation and ICD). Surgical techniques, including ventricular remodelling associated or not to coronary revascularization and mitral annulus reduction are not, so far, applicable in most of these patients in advanced cardiac insufficiency.
This situation suggests then that there is still a real need for mechanical circulatory support systems (MCSS), both in the acute situations and most of all in the chronic advanced cardiac failure.
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2. The systems presently available |
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TopAbstract1. Introduction2. The systems presently...3. The clinical experience4. The futureAppendixReferences |
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These systems use actually different technical options [1]. They may be ventricular assist systems (VAD) using para-corporeal (Thoratec) or intra-corporeal pumps (Novacor or Heartmate I). Each of them is connected to a driver and a control system, which may be included in a large console placed para-corporeally or wearable on a belt. They support either the left (L-VAD) or right (R-VAD) ventricle, or both (bi-VAD). They are based on a well-established technology, the displacement or pulsatile pumps (Thoratec, Novacor and Heartmate) which provide a pulsatile flow.
They may also use more recent pump designs, the continuous flow pumps [2]. These latter pumps are either centrifugal, magnetically suspended (DuraHeart) or axial flow pumps, the rotor being maintained in the correct position either by bearings (Micromed and Heartmate II) [3] or levitating in a magnetic field (InCor Berlin Heart). These innovative pumps provide a continuous blood flow rendering the patient pulseless. This raises the issue of the pulseless circulation, a very unsettled issue for years. It must be said however that if the flow delivered by the pumps is continuous, the pressure curve in the aorta may remain pulsatile if the ventricle is kept ejecting. Finally, despite unanswered questions, these innovative designs are quite appealing because the pumps are small and silent.
The pumps are pneumatically driven, which makes full implantation of the whole system difficult, or electrically powered. Few systems are fully implantable, such as the LionHeart, a left VAD electrically powered and the IVAD, a biVAD pneumatically driven, activated by an extracorporeal pneumatic driver. The non-occlusive pumps are quite appealing in the perspective of fully implantable systems since they do not require the use of a compliance chamber. Each of these systems is implanted after a sternotomy, the heart being eventually supported by the extra-corporeal circulation. The inflow connections are made either in the atria or in the apex of the ventricle. The arterial return is achieved through an arterial outflow cannula connected to the ascending or descending aorta or to the pulmonary artery.
Besides ventricular assist technology which allows a very versatile support in terms of level of flow and ventricular unloading, total artificial hearts are available. Obviously, they permit a total circulatory support only, for a temporary period or a definitive treatment. They are partially implantable and pneumatically driven such as the CardioWest or based on a more recent and innovative technology as in the AbioCor heart: a smaller size is made possible because of the oscillating septum. This leads to a successive ejection of the two ventricles.
Interestingly, most of the present clinical experience has been obtained with systems based on a rather old, well-proven technology (the pulsatile pumps). In the past 20 years, few thousands of patients have received one of these pumps for an average time of more than 6 months. A handful of patients have been living for more than 2 years, up to 4 years, supported by an implantable LVAS. In the mean time, clinical experience with innovative devices (centrifugal pumps) is still both quite limited and very promising. The small size of the devices which permit a better anatomical fit and the lack of noise during assistance is quite appealing. Nevertheless, safety and durability have to be proven by a more extensive clinical experience.
When describing the various technological possibilities, it must be said that the regulatory issues have dramatically slowed the pace of development of systems based on innovative concepts. Each minimal change in design or system must negotiate the difficult path to approval for clinical use. Return on the investment cannot be rapid. It is also questionable if the size of the market is not increased. This might explain why the major companies (the valve and pace maker companies) are staying, so far, away from this technology.
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3. The clinical experience |
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TopAbstract1. Introduction2. The systems presently...3. The clinical experience4. The futureAppendixReferences |
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3.1 The devices
None of the devices presently available is actually fully satisfactory [4]. None of them offers the autonomy expected by the patient: an unlimited period of time free of any connection to either a wearable battery or a controller. None of them enables the patient to have the feeling of a normal life. Most still need a percutaneous cable, connecting the intra-corporeal pump and the driver. In case of a fully implantable device like the LionHeart and the AbioCor, the limited charge of the internal batteries does not allow a prolonged period of real autonomy (less than 30 min). The percutaneous energy transfer system which is a very original feature of these systems has been shown to be effective, but the power of the internal battery has to be improved to allow the real evaluation of the advantages of a totally unfettered life. The issue of the compliance chamber has to be considered: the need of volume adjustment in the system by direct punction of the compliance chamber also contributes to the perception of a total device dependence. This issue of the compliance chamber is actually one of the major reasons to continue the research on systems based on non-displacement pumps as are the axial flow type pumps.
The reliability and durability of available systems are too often an issue. This has been clearly shown in the REMATCH trial [5] which has been designed to compare the clinical performances of an optimal medical therapy to the implantation of a Heartmate LVAS in a population of patients in end stage cardiac failure who had some type of contraindication to the transplantation. About one-third of patients included in the surgical arm have experienced some type of device dysfunction leading to re-hospitalization, need for a pump or replacement of part of the system or death [6]. The high rate of technical problems (pump dysfunction, valve failure) and the less than satisfactory reliability of the system have not helped to convince cardiologists that the technology is actually ready for more extensive use. Even when we consider the most advanced devices such as the AbioCor pump, reliability remains an issue: the cause of death of the only patient who survive long term (517 days) is related to a diaphragm issue. Optimists consider that there is a huge margin for progress. Pessimists will feel that the system has been responsible for the death of too many patients. The optimists have to be considered seriously: the progress has been rapidly shown to be possible by the comparison, in the surgical arm of the REMATCH trial, of the results of the first implantations to the last ones. Survival has been improved and system dysfunction rate has been reduced. The progress is also shown in the results of the Intrepid trial performed with the Novacor LVAS, a more reliable pump than the Heartmate I and in the CUBS study performed with the LionHeart.
The innovative systems based on the use of axial flow or centrifugal pumps have to be shown reliable and safe. This raises the issue of the bearings. Theoretically, one may suspect a higher risk of thrombus formation because of the heating around the bearings and of the mechanical stress. One may also suspect problems related to the fatigue of the materials and the erosion, leading to a displacement of the rotor. Finally, one may wonder about the durability of the electronic components of the system. All these issues have to be addressed scientifically in a strict and precise clinical study. In the bearing less pumps, the stability of the characteristics of the magnetic field has to be proven by a careful analysis of the bearing power during long term implantations.
3.2 The strategies
The real benefit in the therapeutic approach based on the use of artificial ventricles is a crucial issue both in the acute cases and the more stable chronic patients. In the acute cases, in the bridge to transplantation application, where patients have been selected for inclusion on the transplant list, the VAD technology has provided an acceptable answer to the impossibility of a rapid transplantation [7–9]. However, it must also be strongly emphasized that the VAD technology does not provide for this group of patients candidate for a transplantation the final solution to organ shortage since the transplantation is to be performed anyway. Some will even think that it makes patient selection in case of an opportunity of transplantation more difficult, since a choice has to be made between patients stable on a device but exposed to a real iatrogenic risk and the patient perfectly stable waiting on medical therapy.
The bridge to recovery strategy has rarely been the real initial intention to treat. Most often it is, except in the case of acute myocardial ischaemia or acute myocarditis, a retrospective observation, made during attempts at weaning as improvement in ventricular function and the patient's general condition is observed during support. In these patients, the role of associated pharmacological agents in the ventricular remodelling process is still obscure. In addition, diagnosis of the durability of the improvement in cardiac function is difficult to assess prospectively before and after the actual weaning off the pump.
Finally, the evaluation of the benefit of the permanent implantation has to be performed. So far it has been possible only in the few patients with a definitive contra-indication to transplantation who received some type of implantable system. Detailed analysis of the few clinical cases who received this type of treatment shows that the population is made of very sick and old patients. This makes difficult the assessment of the real performances of the system, evaluation of the responsibility of the system in the cause of death or complication [10].
3.3 The patient selection
This is important in the outcome following implantation of any mechanical circulatory system. It may be extremely difficult to achieve correctly in the highly emotional context of a patient about to die, or in a patient who is seemingly a poor candidate for transplantation because of advanced age, as he is hoping for any type of treatment to avoid death. Experience has highlighted the huge difference between the fear of dying and the will for life. The correct assessment of the patient's physical and mental potential to participate in the fight for his own survival remains difficult. These are complex end-of-life issues. Clearly, cardiologists and surgeons are all not ready to handle this issue, the lack of objective parameters making the evaluation particularly difficult.
Besides this fundamental issue, the lack of a definitive prognostic index in an acute or chronic patient makes patient selection difficult. Changes in systolic pressure, serum BUN, creatinine and sodium plasma levels, associated with the response to medical therapy, the limitation in the introduction of full triple medication due to low systolic pressure and/or renal failure have a real prognostic value. Finally, outcome alone will allow a posteriori identification of the correctly selected patient.
3.4 The optimal timing
Optimal timing of the implantation of any device is difficult to define. If too late, irreversible deterioration of the patient's condition may occur; if too early, there may be unnecessary exposure to the risk of device-related complications. Again, despite various attempts of grading the patient pre-implantation condition, there is no definitive objective index to predict the lack of organ recovery following implantation and the return to normal circulatory function. In addition, the exact role of the surgical trauma induced during the implantation and of the initial activation of the inflammatory response related to the disease itself remain unknown. Both nevertheless play an active part in the lack of recovery of major organ function. Again, one must emphasize that the patients selected in the most quoted studies such as the REMATCH trial and the current evaluation of the AbiCor make analysis of the real benefit of the strategy difficult because of the extreme severity of the patients at the time of the implantation.
3.5 The management of the patient
Management of a patient maintained alive on a device remains difficult. The prevention of the infection should be optimized to reduce early and late mortality: the volume of the material to be implanted, size, flexibility and stability of the percutaneous cable at its exit site play significant roles [10]. It may be expected that this infection issue should be reduced by the reduction of VAD size, which allows intra-pericardial placement of the pump and avoids the need for a large abdominal pocket. This has to be confirmed by more extensive clinical studies. Shortening the duration of the stay in intensive care both prior to and after implantation should also help to minimize the risk.
Thrombo-embolism is also a major concern. It ranges from 5 to 35% in the various patient populations. The prevention of thrombo-embolic complications requires better selection of biomaterials, ameliorated design of the assist system itself with improved flow conditions in the inflow cannula, and most of all a better understanding of the mechanism involved [11]. The activation of the vital cascades such as coagulation, fibrinolysis and inflammation, the real impact of the active drugs deserve extensive studies by the specialists. So far, few studies based on solid scientific evidence have been published which permit a significant reduction of this risk.
Finally, much needs to be done to improve the organization of the health care provided in a long-term VAD patient, to optimize nutrition, physical rehabilitation, psychological support and the quality of life. Few centres so far have designed specific protocols that include the patient's demand for more autonomy and correct surveillance of the system. An improved organization and precise protocols should improve the present situation. Education of the patient himself, of his direct environment is a critical issue. In any case, a very pragmatic approach, tailored to the patients' own characteristics appears to be the best alternative, as are progressive changes in the health care with repeated short day trips home, before final discharge.
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4. The future |
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TopAbstract1. Introduction2. The systems presently...3. The clinical experience4. The futureAppendixReferences |
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The lessons learnt over the last 20 years reveal that there is a large margin for improvements in patient selection, infection and thrombo-embolism control, pre- and post-implantation patient management, post-hospitalization care. Each of these issues should be investigated in basic and clinical studies by specialists not yet involved in such evaluations. In other words, a multidisciplinary approach to MCS technology in the clinical arena is necessary.
In the mean time, the real impact of mechanical circulatory support in the management of the patients has to be evaluated by the cardiologists in the various applications: life-saving procedures and temporary use in patients about to die, and elective permanent implantation in well-selected, end stage heart failure patients. It may be assumed that as soon as solid evidence for the safety and efficacy of the device-based therapy is provided by pioneering surgeons in the most difficult patients, acceptance of this new approach by cardiologists and patients will be increased and clinical use extended to patients with less severe disease. Most of the cardiologists believe that the procedure to evaluate a new pharmacological treatment, i.e. a randomized trial, is necessary to demonstrate the benefit of MCS in the class III NYHA patients. This obviously raises the question of the cost of such studies and a second question: who is going to pay for such studies?
More basic research on the real nature of cardiac failure is obviously needed. It might help to understand the reverse remodelling observed so far in the few patients who have been successfully weaned off the pump. It might also help to select from innovative approaches, such as cell seeding and/or gene therapy, new combined procedures to improve the likelihood of return to normal cardiac function.
Finally, the issue of cost-effectiveness has to be addressed. Cost can be easily identified, but effectiveness is more difficult to assess. The end-point of the treatment can be prolongation of life. It can also be quality of life, return to an active professional and social life, time required to reimburse to society the money invested in the patient at a critical time of his life. Cultural and societal considerations interfere with this assessment, as various systems of health care provision play a major role. Clearly these major issues will arise with any novel and expensive therapy implicated in life of death issues.
Only when precise answers are provided to all of these issues will this technology be more readily accepted by patients.
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Appendix |
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TopAbstract1. Introduction2. The systems presently...3. The clinical experience4. The futureAppendixReferences |
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Dr L. Bockeria (Moscow, Russia): There were questions about safety and efficacy studies, innovative pumps, infection, basic research.
Dr Loisance : Yes, there is a lot to do: basic, experimental and clinical research are still necessary.
Dr Bockeria : It was mentioned like key issues.
Dr Loisance : Getting a safe system which is durable, which is compact, silent, is not difficult: it is a matter of technology only. What is more difficult is how to use the systems and how to get a room for the ideal system in the whole armamentarium which is available today in the treatment of cardiac failure.
Dr A. Haverich (Hannover, Germany): The question I have is actually where do you see the main indications for the system for the future? Is it what we have done over the past 10 years, mainly using it as a bridge to transplant? Do you accept one of the systems as destination therapy at this point already, and what would your inclusion/exclusion criteria be? Are there any upper age limits? And what do you think in terms of the number of implants now internationally in Europe, where do they go from now in the various fields of indication?
Dr Loisance : I think we have to accept that the bridge to transplantation approach is a dead end because it does not solve at all the issues of organ shortage. It even makes much more complex the consequence of organ shortage. Consequently, we have the choice of seeking for recovery of the native myocardial function or the destination therapy. The patient could actually be the same.
If during the time of a prolonged period of support the patient shows signs of recovery, then an attempt of weaning will be performed. If not successful, this bridge to recovery obviously becomes a destination therapy. This has to be kept in mind in the process of patient selection at the start. The good patients obviously are not the patients who have multiple organ dysfunction, cachexia, because the road to be covered, at that stage of advancement of the cardiac failure, is too chaotic. We have to accept nevertheless that we will be obliged to start the whole clinical evaluation with this type of patient.
Dr M. Turina (Zurich, Switzerland): A comment and a question. First, about this axial flow device system, MicroMed, which is now generally available. We have substantial experience with this device: one popular myth is that the patients are pulseless. They are definitely not; beating heart provides the pulsatility of approx. 20 to 25 mmHg. So the patients are not pulseless, and that is probably what makes this device so acceptable.
I fully agree with you that the bridge to transplant is a dead end, and only a very small number of patients will become candidates for this method of assistance. Heart failure which we are seeing today is the disease of 70-to-75-year-old patients, and the results of LVAD application in older people are not good. So what is the solution?
Dr Loisance : The solution is a very compact system which can be implantable through a minimal approach, a mini sternotomy eventually, without extracorporeal circulation, and which can be accepted by the patient with a minimum stay in intensive care. That is our experience. We have started using these compact systems in elderly patients above 70, and it makes a huge difference.
Dr Turina : But anticoagulation remains difficult.
Dr Loisance : I fully agree. That is why I said that anticoagulation is probably ‘the’ critical issue, especially for those patients.
Mr B. Keogh (Birmingham, UK): May I ask you a futuristic question? If you look back to the 1950s, heart valves were difficult to put in, they didn't work very well, there were problems with anticoagulation, and I suspect the same sort of discussion went on with people saying, will this ever work? There is part of me that thinks that where there is such a big demand for some kind of therapy for heart failure with an aging population, and we have seen some of the graphs today, do you think it could be that we are being relatively negative about this device therapy and that if we were to look 30 years hence that these may be simply off-the-shelf products which are put in for heart failure?
Dr Loisance : Yes, I am definitely sure you are right. In some years from now, we will have systems which will permit a destination therapy. I don't think it is a matter of 30 years.
If I may comment on that, the surgeons involved in this type of clinical research feel that the worst enemies of mechanical support are the cardiologists. They just don't don't refer the patients to the surgeon. The cardiologists actually are waiting for a device which is safe and gives a good quality of life. They know how to select these patients; we have seen that there are now clear criteria to evaluate the prognosis of the sick patients. The non-supporting people might be the surgical community itself. The surgical community feels that this type of therapy is too complex, too difficult, too cumbersome, the patients are too sick, it keeps your intensive care unit busy for three weeks...There are actually few groups only who accept to invest a lot in this type of therapy.
Dr D. Birnbaum (Regensburg, Germany): Looking to the future, I like an analogy to the past, as you, Bruce (Bruce Keogh), just mentioned in terms of valves. There were many valves on the market, hundreds of them, and there are thousands of papers concerning the technical aspects of the valves, however none has proposed a single solution of the capital restriction of the valve carrying patient. Saying we have now the situation with the devices as a pump resource. We have hundreds of papers about the different techniques, and we don't solve the problem, which is thrombosis. And so, Daniel (Daniel Loisance), what is your feeling about the future of this field?
I think we need a working task group, on the topic of hemostaseology in artificial materials, particularly in the LVADs. So what is your feeling where we should go? Is it thrombelastography for diagnosis; is it genetic production of natural coagulation/anticoagulation participants? What is your answer?
Dr Loisance : Dietrich (Dietrich Birnbaum), I thank you very much for raising this issue, because actually my belief is that if we don't solve the coagulation issue in the coming two years, all the so-called innovative systems will be dead and nobody will accept to use them.
That is why two years ago we started a strong collaboration with L. Drouet, a specialist of the platelets and coagulation. We had a very active discussion about the implication of his group in the field of mechanical circulatory support. The discussion was blocking on the fact that the numbers of patients are minimal. Actually, these specialists in coagulation realized that it this population gives a unique opportunity to evaluate the pathophysiology and the actions of the new molecules. Finally, the good thing is that they are now bringing to us their knowledge of the platelet receptors and the tricky action of various drugs.
We are supposed to be smart, but when you are talking with these coagulation-specialist, you may feel very stupid. They know much more than us and nevertheless we have been trying for years to play by ourselves with potent drugs like Plavix: 25 or 75 mmg per day! This is ridiculous. It is like giving a machine gun to a child: you kill the patient and you don't know why.
By getting the support of the specialists, we have totally changed our anticoagulation protocol, and so far the patients bleed less and don't die of embolism. We see the progress, and this confirms that we definitely need to have the expertise of the people who know. Now, the bridge between these specialists and us is made. Every week we have staff meetings and every patient is discussed. Adjustment of each individual treatment is made according to the results of their sophisticated tests and the clinical situation. It is not anymore a matter to know if the surgeon has to buy a new aggregometer, which one is the best, and which parameter of the TG we should consider. It is not our job. We have to ask the people who know, and to get them on board. We have to get them excited. They are now extremely excited, for the patient best benefit.
Dr F. Beyersdorf (Freiburg, Germany): I would like to make two comments. First, you mentioned the REMATCH trial, and I think one has to remember that the TCI system which was implanted was never ever designed for permanent use. The study is wrong in the beginning. They implanted the device for permanent use, which is only designed to be a device for a bridge to transplant, meaning implantation times of, whatever, 50, 100 days or so on. So to implant a device which is only designed for a couple of months, to implant them until all patients are dead is difficult, let's say, everywhere.
Dr Loisance : I agree, but if you believe there is a good car, then you try to drive it as long as possible.
Dr Beyersdorf : That's right. But that is the reason why all these devices fail at the end because that is what they are, they just fail.
The second thing is I think we should not forget that let's say 10 years ago almost all patients who received a mechanical assist device almost all died, one way or the other. Today, we have made huge progress. I mean, for example, the last 30 or so TCI patients, almost 90% survived, with transplantation, of course, that's right, but there has been tremendous progress made, even though I agree with you completely, it is far away from being perfect or easy or whatever.
But maybe it is something for the very sick patients in the future that we have to combine, first of all, to have a device which does not need coumadin or anything, for example, the surface thing from the TCI system. Second, we might combine LV restoration during implantation of the assist device and then add stem cell therapy to it. Maybe Professor Hescheler is going to talk about this a little bit.
So I think we should just see where we are and see that this is a potential for the future to be further involved. And your comment, Bruce (Bruce Keogh), about the valves is very good. Of course, the assist devices are much more complicated than a valve and it will take maybe even longer, but we have made progress and we will see where the future is. But we as surgeons are at a point where we are able to treat heart failure better than anybody else with whatever technique, with restoration, with an assist device, with mitral valve surgery, whatever, and we should clearly intensify our efforts to treat heart failure patients.
Dr Loisance : You are very right. In the cardiological medical community they now accept that cardiac failure may be become a surgical disease, and the only question they are asking is, when should they refer the patient to a surgeon? They have moved from 20 years ago when there was no real active treatment of cardiac failure. So there is huge progress which has been made.
Again, a lot as to be done to know the optimal way to use the pumps. The role of new medical therapies, of cell seeding combined to mechanical support has to be evaluated. I tried in my talk to look to the roads opened by the analysis of the present stage of development of the technique. I don't think we are there to sit down and say that we are the best. There is a lot to be done.
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Footnotes |
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Presented at the EACTS Symposium for the Future of Cardiac Surgery, Frankfurt, Germany, July 1–2, 2004. |
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TopAbstract1. Introduction2. The systems presently...3. The clinical experience4. The futureAppendixReferences |
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