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Heart Transplantation and the Total Artificial Heart |
Heart Transplantation and the Total Artificial Heart Matthew Stratmann Advanced Placement English IV Iskra, p. 1 February 28, 2005 Introduction Over the course of the last two centuries, heart disease has become a widespread condition of epidemiological proportions. “Almost 4.8 million Americans are living with congestive heart failure,” CHF, and 875,000 more cases are diagnosed each year in the United States alone (Frazier 1). Of these, one in five with be diagnosed with primary or secondary heart failure and 400,000 will die within five years of diagnosis. Heart transplantation and the total artificial heart offer a potential cure to many forms of end-stage cardiac disease, including congestive heart failure. The History of Heart Transplantation and the Artificial Heart Many decades of research preceded the first successful cardiac transplantations, a vision carried well into the present and future. Highly invasive procedures such as open heart surgery were difficult to perform and maintain until the mid-1900s with the discovery of ether and chloroform as effective general anesthetics. “The birth of heart transplantation can be traced back to innovative French surgeon Alexis Carrel, who performed the first heterotopic canine heart transplant with Charles Guthrie in 1905,” (Bethea 3). This early demonstration of the future potential of human heart transplantation was performed by removing the original canine heart from the cardiopulmonary circuit and restoring circulation with another species-specific heart implanted nearby. The procedure was not fully successful as the donor heart become aggressively inflamed and damaged from an unknown source within the recipient’s body. Frank Mann, of the Mayo Clinic, wrote that “failure of the donor heart to survive is not due to the technique of transplantation…but to some biological factor,” (Hoffman 51). Donor tissues are viewed as foreign materials by the host’s immune system and progressively attacked by leukocytes, leading to inflammation of the localized area and necrosis (tissue death) of the unrecognized matter. In the case of heart transplantation the myocardium, or muscle layer of the heart, degenerates rapidly as nutrients cease to be metabolized and white blood cells induce lysing. Vladimir Demikhov, of the Soviet Union, demonstrated the first intrathoracic heterotopic transplantation. Unlike Carrel and Guthrie, Demikhov tried a new approach to bypassing the host heart by “placing the donor heart above the [original] heart” until explanation [removal of the original heart] was completed (Stephenson 37). Demikhov is also credited with suggesting the first complete heart and lung transplants as well as minor lung transplants as future possibilities. Primarily due to a lack of the necessary methods or technology to allow cardiopulmonary bypass, most modern forms of cardiac surgery such as transplantation were not feasible until the advent of the heart-lung machine in 1952 by a team led by Forrest Dodrill. In fact, “the development of medical devices like the pacemaker, artificial heart valves, the heart-lung machine, and pump oxygenators all preceded and influenced different versions of the artificial heart,” (Hoffman 83). Shumway and Lower, of Stanford University, used the research of Carrel, Guthrie, and Demikhov to take yet another major step in reaching a full heart transplant by excising the host heart and fully replacing it with the donor heart. Several methods such as lowering body temperature and fully bypassing circulation during surgery using the heart-lung machine provided new insights towards performing the procedure on human rather than animal subjects. 1964 marked the year of the first transplant using a human subject, performed at the University of Mississippi by James Hardy. Incidentally, this procedure also brought the use of xenotransplantation, the use of an organ from another species, into serious consideration within the medical field. Using the orthotopic transplantation procedure developed by Lower and Shumway, Hardy replaced a human heart with a chimpanzee heart. The procedure was a success from a surgical standpoint; however, the donor heart was “unable to support the circulation due to hyperacute rejection” (Stephenson 37). Due to the difference in cell surface markers (proteins and carbohydrates which identify a cell), the recipient would have rapidly rejected the donor heart regardless of the procedural success. In order to counter the barrier of rejection, Phillip Caves created the transvenous endomyocardial biopsy for allografts in 1973. Through this procedure, a small biopsy tool could be maneuvered into the heart using one of the major veins as an access point in order to retrieve a small tissue sample from the inner heart chambers. As a result, physicians were provided with a simple tool to evaluate patient rejection of allografts, or “tissues transferred from one individual to another of the same species,” (Griffith 2). In 1981, a major breakthrough in patient survival and transplant viability was discovered in cyclosporine, an effective drug used as an immunosuppressant. Using cyclosporine, it became possible to slow the rate of rejection and allowed preventative measures to be exercised in the time before the donor tissues became irreparably damaged. Armed with the ability to monitor and treat patients receiving allografts, the medical field ushered in the modern methods and techniques of heart transplantation that are still widely used today. The total artificial heart followed a similar path of development, eventually becoming the “bridge” between biological transplantation of the human heart and even a complete alternative. LeGallois is credited with first suggesting that the human heart could be supported or even replaced by a mechanical device in 1812 (Frazier 3). However, the technical abilities and underdevelopment of the medical field in that time period would not permit for significant advances in LeGallois’ vision until the early 1920s, at which point thoughts of the heart-lung machine began to surface. In the early 1930s, Charles Lindbergh, the American aviator, and Alexis Carrel began research to produce a perfusion pump or heart-lung machine that could sustain organ life indefinitely. A working model was produced in 1935; however, difficulty in operation and effectiveness forced the Carrel-Lindbergh model into obscurity by 1940. Following World War II, Dennis and Gibbon ushered in the era of modern mechanical circulatory support (MCS) in 1951 by using a heart-lung machine in an open heart surgical procedure. Low success rates forced the innovative machine to be abandoned until a more refined version was developed, the Mayo-Gibbon machine. Between 1955 and 1960, Kirklin, Lillehei, DeWall, Dennis, and Gibbon had refined their respective versions of the heart-lung machine, making open heart surgery an almost routine activity in many parts of the United States (Frazier 3). In 1957, Akutsu and Kolff implanted the first total artificial heart into a living organism, but failed to apply their technique to human subjects. Having read of Akutsu and Kolff’s success, Debakey implanted a mechanical pump-assist device into the left ventricle of a human in 1963. Motivated by a lower mortality rate and the immunosuppressant cyclosporine, physicians began to research a far more ambitious invention, the human total artificial heart. The first artificial heart was implanted by Cooley in April, 1969 as a substitute until a biological heart could be transplanted. This new device, created by Liotta, was pneumatically powered with valves to prevent backflow of blood into the veins. Although successful in clinical trials, this new device was rejected by medical practitioners until a similar device, the Akutsu-III, was created and tested in 1981 (Frazier 5). In July, 1981, Cooley performed the second transplantation of a total artificial heart into a patient suffering from end-stage cardiac failure following an aborted bypass (a procedure in which other veins/arteries are used to bypass the original structures) . Unlike Liotta’s heart, the Akutsu-III was designed with two chambers in each of the pneumatic pumps, resembling the atria and ventricles of the human heart. Also used as a bridge to transplantation, the Akutsu-III minimized complications such as hemolysis and thromboembolism which had forced many prior patients into submission. Kolff continued his research throughout the 1970s following his success in 1957, eventually producing the Jarvik-7 TAH. DeVries implanted the first permanent Jarvik-7 in 1982, intended as a replacement rather than a bridge for transplantation. Unfortunately, the design of Jarvik-7 suffered much of the same complications that had plagued prior TAHs. Monitoring devices, pumps, and pneumatic drivelines maintained extracorporeal contract with the implanted device and limited patient activity, leading to sepsis (infection) and organ failure (Frazier 7). A similar version of the Jarvik-7, the CardioWest TAH, enjoyed continued use in the early 1990s as a highly effective bridge to transplantation. The most modern development in mechanical circulatory support came in 2001 with the unveiling of the AbioCor TAH. Unlike its similar predecessors, the AbioCor TAH is capable of being monitored and powered by a transcutaneous system, significantly decreasing the likelihood of fatal sepsis. Radio Frequency (RF) communication supplies the TAH with instructions as well as the ability to monitor pump function. A Transcutaneous Energy Transfer (TET) device transmits the necessary power through the skin without any direct external or internal communication (Frazier 8). Despite many breakthroughs in bridging transplantation and the Total Artificial Heart, immunological rejection, infection, and hemolysis still continue to prevent the total recovery sought by the medical field. Anatomy and Physiology of the Heart: The heart is located within the mediastinum, the hollow formed by the curvature of the right and left lungs, below the sternum. Most of the heart’s mass lies to the left of the midline, occupying the space of the left lung’s absent third lobe. “Anteriorly, the heart is covered by the sternum and costal cartilages of the third, fourth, and fifth ribs,” which provide protection to the invaluable tissues below (Mill 3). Additional cushioning and protection is provided by a dense “sac” of connective tissue known as the pericardium which surrounds the heart. The pericardium is also responsible for anchoring the heart to the surrounding tissues and preventing blood from overfilling the heart during exercise and activity. Two layers of tissue, known as the parietal pericardium and visceral epicardium, line the inner walls of the pericardium. Serous fluid fills the pericardial cavity and prevents friction caused by the cardiac motion cycles and movement of the lungs during inhalation and exhalation. Several major vessels critical to the success of open heart surgery and transplantation lie within the pericardium and provide nutrients to the myocardium as well as communication with the lungs and body. The two largest veins of the body, the inferior and superior vena cava, lie posterior to the right dorsal portion of the heart and supply deoxygenated blood to the left atrium. This deoxygenated blood is pumped from the right ventricle into the pulmonary trunk, which communicates directly to the lungs through the left and right pulmonary arteries. Oxygenated blood returning from the lungs travels through the pulmonary veins, which in turn empty into the left atrium. Blood is then pumped to the aorta, where it can be transported to the major organs and bodily tissues. Two smaller vessels, known as the left and right coronary arteries directly communicate into the junction of the aorta and left ventricle, supplying the heart with a rapid flow of oxygen and nutrients. The heart is directly composed of three primary layers; the epicardium or visceral pericardium, the myocardium, and the endocardium. The epicardium forms the outermost layer of the heart and inner layer of the pericardial sac. The myocardium is the thickest layer of the three and “is the layer that actually contracts” (Marieb 684). The final, innermost layer of the heart is the endocardium, made up of simple squamous (flat, sheet-like) protective cells which form the inner lining, or endothelium, of the blood vessels. The heart is divided into 4 separate chambers: two atria and two ventricles. The right and left atria serve as entry points for blood into the heart and pump blood into the ventricles. The right and left ventricles pump blood out of the heart. “This one way traffic [of blood] is enforced by four heart valves: the paired atrioventricular and semilunar valves” (Marieb 690). The tricuspid valve guards the passage of blood between the right atrium and ventricle and the pulmonary semilunar valve forms the junction of the right ventricle and pulmonary trunk. Blood enters the left ventricle, passing through the mitral valve, before leaving the heart by means of the aortic semilunar valve. Bridge to Transplantation and the Total Artificial Heart By far one of the greatest setbacks to heart transplantation, the incredibly small amount of donor organs severely limits the number of heart transplants that can be performed each year. “Approximately 2,200 [heart transplants] per year” are performed in the United States (Bethea 4). However, there is a virtually limitless supply of expensive, but readily available, Total Artificial Hearts. With respect to end-stage heart failure, the artificial heart is not comparable to a successful allograft transplant in terms of life expectancy and quality of living. While still falling short in performance, the alternative is often death. Instead, these devices are becomingly increasingly successful as temporary bridges to transplantation and permanent implants to patients who are not qualified for heart transplantation. Each year the number of end-stage heart failure cases increases dramatically as does the “waiting” list for potential heart transplantation. “At any given time, almost 3,500-4,000 patients are waiting for heart or heart-lung transplant…More than 25% do not live long enough” (Heart and Lung Transplants 2). The total artificial heart offers the possibility of an extended life span until a more permanent solution can be provided for patients who have been approved to receive a donor allograft. In short term one-year trials, the artificial heart proved to be rehabilitative and actually increased the health of the host body. Almost seven out of ten patients receiving the Total Artificial Heart as a mechanical bridge to transplantation underwent successful transplantation and, of these, eight out of ten are expected to survive beyond one year. As described, the process for choosing the recipients of donor allografts is highly selective and eventually excludes thousands of terminally ill patients. In these cases, the artificial heart may be implanted permanently. Unlike a biological heart, the artificial heart requires electrical power and is composed entirely of synthetic materials. Therefore, complications due to arrhythmia and hyperacute rejection are a minimal consideration. However, the Total Artificial Heart suffers several major drawbacks which cumulatively make it inferior to an allograft. “Postoperative bleeding…generally occurs in 40% to 50% of TAH or ventricular assist device recipients,” (Frazier 11). The direct anastomosis (joining) of organic and inorganic blood vessels can lead to inflammation and internal bleeding, resulting in rejection of the artificial heart or death. The non-biological valve components of the artificial heart are also highly susceptible to clot formation. Damaged red blood cells may accumulate into thrombotic deposits or embolisms, leading to septicemia, atherosclerosis, stroke, and multi-organ failure. Donor Heart Procurement and Selection The donor heart must be excised and placed in myocardial stasis within minutes of donor organ failure to prevent permanent ischemic injury. “Unlike skeletal muscle, [the myocardium] cannot incur much of an oxygen deficit and still operate” (Marieb 696). While remaining in the host body, the heart continues to draw upon oxygen and nutrients in a high level of activity. Unless slowed, necrosis of the myocardium may occur within minutes. A network of specialists, researchers, and surgeons known as the organ procurement team remains on standby until the donor is proclaimed dead. The donor is surgically prepared in the same methods as a living patient with the exception that no anesthetics or vasoactive agents are administered to prevent drug interactions in the recipient. An incision, known as the median sternotomy, “is made from the jugular notch to just below the xiphoid process,” separating the presternal fascia and subcutaneous tissues (Mill 5). Once the sternum has been divided and spread, an anterior incision to the pericardium is performed to reveal the epicardium and caval junctions. The connective tissue anchoring the vena cavae and the azygous vein must first be incised, mobilizing the respective vessels. All three vessels are subsequently ligated, leaving a large amount of the superior vena cava intact. Intravenous heparin is administered to prevent clotting and insure the viability of the donor organs. A cardioplegic, or “heart stopping,” solution, consisting of a high volume of potassium ions, is injected at the branch of the innominate artery and exits the heart through an incision of the inferior vena cava. A second solution consisting of highly dilute saline floods the pericardial cavity, bringing the heart to an approximate temperature of 27-28 degrees Celsius. The chemical properties of potassium temporarily immobilize the actin and myosin filaments responsible for heart contraction, while the lowered temperature decreases cellular metabolism. The second, and crucial, part of the donor cardiectomy occurs at the sectioning of the atria and pulmonary veins. Variances in each procedure are employed, depending on the condition of the recipient’s great vessels and communicative junctions. Appropriate incisions are employed to “retain adequate atrial cuffs,” (Bethea, 14), facilitating anastomosis of the pulmonary arteries and atria. The aorta and remaining great vessels are divided either distally or proximally to the respective cardiac junctions depending, on the condition and extent of pathological damage to the recipient vessel network. Following ligation, the donor heart is examined for anomalies and valvular deformities to prevent unforeseen complications during implantation (Savage 1). Once the donor heart is successfully explanted, it is placed in hypothermic stasis at approximately 5-8 degrees Celsius to further slow the metabolism of the myocardium and neural fibers. Before implantation can be successfully performed, the donor heart must be tested for compatibility to prevent hyperacute rejection. The first and primary set of criteria for the donor heart is blood typing and body size. Fatal rejection rapidly occurs should the donor heart come from a host body of an incompatible blood type. Body weight and size must also be considered in selection of a potential heart for transplantation. As demonstrated by Hardy’s xenotransplantation procedure in 1964, the donor heart varies in size and strength, depending on the mass of the host body. A small heart such as that of a 10 year old child would be unable to sustain the blood pressure and circulation necessary in an adult, resulting in hypotension and circulatory failure. Likewise, an adult heart implanted into a child would provide excessive pressure, resulting in aortic hemorrhage and death. Modern criteria states that donor weight among adult donors and recipients must not vary by more than 30%. For children and infants the range of acceptable weight difference is significantly smaller due to the continuing development of vital organs and post-operative fragility of the aortic junctions. Once the primary criteria have been met, the donor heart is tested for immunological and histological incompatibility. Compounds collectively known as Human Leukocyte Antigens, or HLAs, “are the major targets in transplant rejection” (Cotran 210). HLA antigens are divided into two categories, known as class-1 and class-2. Class-1 antigens, HLA-A and HLA-B, are primarily matched to insure short-term compatibility among related donors and recipients. Secondary HLAs identified as class-2 are critical to matching among unrelated donors and recipients by preventing activation of the cell-mediated immune mechanisms. Tertiary antigens not included in the HLA subclasses will differ “except in the case of identical twins” (Cotran 210). The minor antigen-antibody interactions found on this level are easily controlled with cyclosporine and do not present a threat to the short-term success of transplantation. Cyclosporine or other immunosuppressants may be administered pre-operatively and post-operatively to decrease the chance of hyperacute rejection. Allograft Implantation Procedure An approximate “period of four to six hours” (Bethea 18) is allowed before the donor heart suffers permanent damage. Virtually all histocompatibility matching must be completed prior to beginning the opening procedures of heart transplantation. Once the organ preservation and procurement team has confirmed a successful match, the patient, notified and surgically prepared, is admitted into the operating room. Given the decreasing amount of time before the donor heart expires, the preoperative and perioperative procedures must be synchronized with the arrival of the donor heart to minimize the amount of myocardial and nervous damage. The organ procurement team signals that the donor heart should arrive by the completion of the recipient heart excision, allowing for a complete transition from explantation to implantation with minimal bypass trauma. The most commonly used method of gaining access to the thoracic cavity is the median sternotomy. An incision is made from the jugular notch to the xiphoid process of the sternum, separating the presternal fascia and subcutaneous tissues. The avascular midline plane must be utilized in order to prevent excessive hemorrhage into the mediastinal space. Once the sternum has been divided and spread, an anterior vertical incision into the pericardium is performed, revealing the epicardium and myocardium. Unlike excision of the donor heart, the recipient must undergo cardiac bypass prior to removal of the original heart. “Bicaval venous cannulation [insertion of a tube into both vena cavae] and distal ascending aortic cannulation just proximal to the origin of the innominate artery is optimal” (Bethea 18). Blood which normally enters the heart through the inferior and superior vena cava is shunted to a nearby cart, which oxygenates and returns blood through the distal ascending aorta. If necessary, the flow of oxygen and nutrients through the bypass device may be altered to control the metabolic rate of the patient. Once bypass has been initiated, the recipient body is cooled to a temperature of 27-28 degrees Celsius in order to prevent accumulation of metabolic wastes and nutrient deficiency. With bypass successfully established, the recipient’s original heart is effectively removed from the cardiothoracic circuit. The same procedures employed in donor heart retrieval are used to excise the damaged tissue. However, the original atria remain largely intact to prevent post-operative arrhythmia. The aortic arch is separated along the semilunar commissures and the heart is removed from the pericardial well. If no major setbacks are encountered by the organ procurement team the donor heart should be ready for transplantation. Prior to being orthotopically placed within the pericardial well, the donor heart must be soaked in cold saline and excess tissue is removed to match the recipient’s atrial cuffs. The aorta and pulmonary artery are separated from the donor heart and the pulmonary vein orifices are sutured together to create the left atrial cuff of the graft. The allograft is then placed within the pericardial well with a layer of cold sponge between the warm host tissue and the preserved heart to prevent necrosis. Prolene, a strong polypropylene surgical mesh, is placed through each of the atrial cuffs. Irrigation with cold saline is maintained around the ventricles continuously throughout the atrial anastomosis. Beginning at the level of the superior pulmonary vein, a suture is placed in a continuous method towards the midline portion of the donor atrial septum. A second suture completes the anastomosis on the superior aspect of the left atrium and finishes at the level of the completed first suture (Bethea 2). The patient must be elevated and shifted to the left to allow flooding of the inferior portion of the pericardial well and to provide a clear operational area. Another suture is placed at the uppermost portion of the atrial septum and continues until both ends of the suture meet at the level of the foremost right atrial wall. Both pulmonary arteries are joined in a similar fashion, with the suture anchor placed in the posterior arterial wall from the interior and completing at the anterior wall from the outside. Saline irrigation is stopped to allow a gradual heat transfer between the donor heart and aortic anastomosis is completed with a small amount of excess donor tissue untrimmed. The arterial cannulations are removed and bypass is safely discontinued. Intravenous inotropes, drugs which support heart contraction and strength, are administered prior to innervating the transplant. Vents are placed at the inferior level of the aorta and pulmonary arteries to allow potentially fatal air pockets to be removed. Electrocardial rhythm is restored and stabilized using the inotropic medication and the pericardial incision is closed. The initial median sternotomy is closed using a running suture of wire mesh, ending at the level of the xiphoid process. Provided the patient is restored to regular cardiac rhythm and showing no signs of trauma, the transplantation team retires from the operating room. The Immune System and Postoperative Transplant Rejection The immune, or lymphoid, system is responsible for preventing infections and maintains the general health of the human body using a variety of components. The primary leukocytes (white blood cells) of the blood-based immune system are the macrophages, neutrophils, eosinophils, and natural killer cells. Macrophages are large cells which are specialized versions of monocytes which have migrated into the tissues. Neutrophils and natural killer cells are also associated with phagocytosis (ingestion of the foreign object or infected cell), whereas eosinophils are more commonly identified with parasitic infections. Non-cellular or humoral proteinaceous components of the immune system (known as antibodies) circulate in the blood and are the primary activators of the rejection response (Immune 13). All cells contain specific methods of identification, known as cell surface markers, which are unique to each species and individual. The immune system uses these compounds to distinguish foreign invaders from normal cells and reacts proportionally to the degree of variance from the hosts own cell markers. Cell surface markers differ depending on the genetic identity of the host body. As a result, allografts, or human donor grafts, are usually more compatible than xenografts (grafts from another species). Allografts, therefore, are less likely to experience pathogenic immunorejection as compared to xenografts. Unlike grafts, prosthetic devices and implants such as the total artificial heart have no surface markers. But, an absence of markers also activates the immune response. In both cases, “mismatched” identification leads to two similar, but separate, rejection processes. The immunorejection process for allografts and xenografts begins when specialized proteins within the blood, known as antibodies, bind to foreign cell markers. Lymphocytes and cytotoxic t-cells are attracted to the site where an inflammatory response develops. In heart allografts and xenografts, the rejection process is characterized by vasculitis and subsequent vascular degeneration. If left untreated, fatal rejection occurs. At this advanced stage, blood hemorrhages into the interstitial space from vascular damage and myocardial necrosis rapidly follows. Chemical and cellular debris from lysed cells attract a high presence of “inflammatory infiltrate…in response to myocyte necrosis or vascular damage” (Schoen 77). The extent of rejection is primarily determined by the progression of damage to the blood vessels. Oxygen and nutrients gradually become unavailable to the graft and, in the case of a heart transplant, widespread ischemic damage (damage specifically caused by a lack of oxygen) occurs within the myocardium. Unsuccessful attempts to reverse this process lead to advanced rejection, which “may be irreversible and fatal” (Cotran 598). The artificial heart contains none of the biological markers or structures that leads to an immunologic response and therefore must follow a different path to rejection. The total artificial heart elicits a “nonimmune inflammatory response” from the host known as a foreign body reaction (Schoen 18). “Antibodies and many of the highly specialized leukocytes are unable to interact with the metal or plastic surfaces” (Snider), rendering the primary mechanisms of immunity completely ineffective. Instead, the body recognizes the matter as foreign and activates inflammation of the tissues in the immediate vicinity of the foreign material. Cells such as monocytes, macrophages, and multi-nucleated foreign body cells gather in high concentrations to maintain the inflammatory response in an attempt to ingest the inorganic material. However, the host’s cells are unable to employ phagocytosis against the foreign material and must resort to a different tactic. Eventually, “a tissue layer composed of collagen and fibroblasts forms between the biological and artificial surfaces” (Snider). In some cases the inflammatory response is sustained for weeks or even years, sensitizing the body to the presence of the transplant. Greater sensitivity causes a proportionally increased inflammatory reaction. If the reaction is unsuccessfully repressed, the artificial transplant must be removed to prevent irreversible and possibly life-threatening damage. Conclusion and the Future of Heart Transplantation The success and performance of heart transplantation has greatly improved since its original conception and will most likely to continue far into the future. Less than two decades ago, heart transplantation was a final attempt at saving terminally ill patients with a dismal success rate and an even less promising prognosis. Now, after twenty years of advances in the medical field, heart transplantation is a routine, though limited, procedure, capable of granting extended life to thousands of recipients worldwide. In order to supplement the shortage of donor hearts, which is the intrinsic setback of human allograft usage, a new field of cardiology has evolved with the goal of providing an equivalent artificial heart. At present, the artificial heart is not considered a viable alternative to a biological graft and is primarily used as a bridge to transplantation. The latest of these devices, the Abiocor TAH, “may become a widely used alternative to heart transplantation for those patients who have no other treatment options.” (Frazier 13). Given the pace at which biological orthotopic heart procedures developed, it is only a matter of time before the Total Artificial Heart becomes a final cure to end-stage heart failure. Works Cited Bethea, Brian T. et al. “Heart Transplantation.” Cardiac Surgery in the Adult. Cohn, LH, Edmunds LH Jr, eds. McGraw-Hill, 2003 New York 12 October 2004 http://cardiacsurgery.ctsnetbooks.org Cotran, Ramzi S. et al. Robbins Pathologic Basis of Disease 6th Edition. Philadelphia: W.B. Saunders Company, 1999 Frazier, O.H. et. Al. “Total Artificial Heart.” Cardiac Surgery in the Adult. Cohn, LH, Edmunds LH Jr, eds. McGraw-Hill, 2003 New York 12 October 2004 http://cardiacsurgery.ctsnetbooks.org Griffith, Bartley P. and Poston, Robert S. “Immunobiology of Heart and Heart-Lung Transplantation.” Cardiac Surgery in the Adult. Cohn, LH, Edmunds LH Jr, eds. McGraw-Hill, 2003 New York 12 October 2004 http://cardiacsurgery.ctsnetbooks.org “Heart and Lung Transplants.” Medical College of Wisconsin. 6 July 1999. 13 October 2004. http://healthlink.mcw.edu Hoffman, Nancy. Heart Transplants. United States: Lucent Books, 2003. “Immune System.” March 19, 2003 8 October 2004 http://cchavax.hartford.edu Marieb, Elaine N. Human Anatomy and Physiology. San Francisco: Benjamin Cummings, 2001 Mill, Michael R. et. al. “Surgical Anatomy of the Heart” Cardiac Surgery in the Adult. Cohn, LH, Edmunds LH Jr, eds. McGraw-Hill, 2003 New York 12 October 2004 http://cardiacsurgery.ctsnetbooks.org Savage, Edward B. “Heart Transplant Donor Retrieval Protocol.” Adult Cardiac Experts’ Techniques. 2001. October 13, 2004. http://ctsnet.org/doc/3307 Schoen, Frederick J. and Padera, Robert F. “Cardiac Surgical Pathology.” Cardiac Surgery in the Adult. Cohn, LH, Edmunds LH Jr, eds. McGraw-Hill, 2003 New York 12 October 2004 http://cardiacsurgery.ctsnetbooks.org Snider, Michael. Personal Interview. 20 October 2004 Stephenson, Larry W. “History of Cardiac Surgery” Cardiac Surgery in the Adult. Cohn, LH, Edmunds LH Jr, eds. McGraw-Hill, 2003 New York 12 October 2004 http://cardiacsurgery.ctsnetbooks.org |
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The work contained herein is freely accessible and may be used as references. However, PLAGIARISM IS STRICTLY PROHIBITED and copyrighted sources within my works must be given the same considerations. |
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