In the early 1900s, many considered the repair of blood vessels an impossibility. Alexis Carrel, MD (June 28, 1873–Nov. 5, 1944), led the way in small vessel vascular surgery, which promoted organ transplantation [6]. As a medical student, Carrel first became interested in vascular anastomosis after the president of France died from a laceration of the portal vein. At the time, the death of the president was believed inevitable because the procedure to repair blood vessels was unknown [6]. Dr. Carrel reviewed experiments by Mathieu Jaboulay that involved the repair of divided carotid arteries with an everting mattress technique. This technique was not reproducible on small vessels so Carrel began working on vascular anastomotic experiments and published a manuscript on his technique in 1902 [5, 6].

After he experienced a minor setback in his medical career, Dr. Carrel moved to Chicago in 1904 and began work with Charles Guthrie, MD (Sept. 26, 1880–April 1963), at the University of Chicago [5–7]. There he refined his triangulation method of vascular anastomosis using fine needles and sutures treated with petroleum jelly. While at the University of Chicago, Drs. Carrel and Guthrie demonstrated that veins could be used as a viable substitute for arteries by replacing sections of carotid artery with the jugular vein [5, 6]. They also proved that a vein patch could tolerate arterial pressures. Using these techniques, they published a manuscript in 1905 detailing the successful transplantation of a dog’s kidney into the neck of another recipient dog using these refined surgical skills [5, 6]. The kidney functioned normally after transplantation; however, the dog died later of infection. Drs. Guthrie and Carrel subsequently transplanted the thyroid gland, kidneys, and ovaries from one dog to another as well as the heart of a small dog into the neck of a larger dog with witnessed contractions following implantation .

In 1906, Dr. Carrel moved his research to the Rockefeller Institute in New York [6]. There he established that blood vessels could be preserved in cold saline for days to weeks, reimplanted, and maintain their function. This was his entry into experiments on tissue preservation—so important in organ transplantation. Dr. Carrel pursued different methods of tissue and organ preservation such as heating and dehydration and storing tissues in glycerin, formalin, or petroleum jelly. By 1909, Dr. Carrel had successfully transplanted other organs in animals, such as the adrenal gland, spleen, intestine, heart/heart-lung block, and limbs [5, 6]. His groundbreaking work focused on transplantation earned him the Nobel Prize in 1912.

In 1929, he developed protocols for organ perfusion. These initial experiments failed due to infection of the perfused organ. With the aid of renowned pilot Charles Lindbergh (Feb. 4, 1902–Aug. 26, 1974), who became a close friend and colleague, Dr. Carrel developed the first functional pump oxygenator 5 years later [5–7]. Together, Dr. Carrel and Lindbergh coauthored a book, The Culture of Organs, and they appeared on the cover of Time magazine (1938) (◘ Fig. 25.3).

In the 1930s, Frank Mann, MD (Sept. 11, 1887–Sept. 30, 1962), uncovered allograft rejection by examining failing heart transplants in animal models [8]. His seminal studies with heart transplantation examined implantation of the denervated heart of dogs. He found that the transplanted heart began to beat after coronary blood flow was established. The donor heart survived an average of 4 days [8]. The longest survival was 8 days. He noticed that every graft failure was caused by cardiac distention before a rhythm was established. Therefore, graft protection included avoidance of air embolism and ventricular distention. Once the donor heart was at the end of its lifespan, Dr. Mann examined the removed heart and found [5, 8]:

The surface of the heart was covered with mottled areas of ecchymosis; the heart was friable on section. Histologically the heart was completely infiltrated with lymphocytes, large mononuclears and polymorphonuclears… it is readily seen that the failure of the homotransplanted heart to survive is not due to the technique of transplantation but to some biologic factor which is probably identical to that which prevents survival of other homotransplanted tissues and organs.

This observation would later prove valuable to our understanding of graft rejection and immunosuppressive therapy .

Twenty years later, at the Chicago Medical School, work on another piece of the puzzle started to progress: graft preservation [5, 9, 10]. Drs. Marcus, Wong, and Luisada tried using a third dog to support the donor heart until implantation [5]:

The method we have called interim parabiotic perfusion; it is a homologous extracorporeal pump.

Unfortunately, the donor heart only survived 48 h. Another group from Hahnemann Medical College—Drs. Wilford Neptune , Charles Bailey, and Brian Cookson—also made strides in 1953 toward graft preservation [5, 7]. They used hypothermia of the donor heart, but only achieved a 6-h survival time when transplanting both the heart and lungs into dogs.

Although Dr. Vladimir Demikhov’s work was not available in English until the early 1960s, Demikhov (July 18, 1916–Nov. 22, 1998) began making advances in heart transplantation in the late 1930s [5, 7, 10]. As a student in 1937, he engineered the first mechanical assist device and was able to support the circulation of an animal for 5.5 h with the heart excised. Due to WWII, there was a break in Demikhov’s research, but in June 1946, he performed a heterotopic heart-lung transplant in an animal thorax. The animal survived 9.4 h. In 1951, he performed the first orthotopic heart transplant in an animal. Through the mid-1950s, he completed 22 orthotopic heart transplants without cardiopulmonary bypass by using sequential anastomoses to maintain perfusion throughout the procedure [5].

During one of his experiments in January 1955, he ligated the recipient’s great vessels and closed the mitral valve so the recipient was exclusively dependent on the transplanted heart. The dog survived for 15.5 h. Death was secondary to thrombosis of the superior vena cava. From 1946 to 1958, Vladimir Demikhov performed 250 heart transplants in animal models, achieving survival up to 30 days [5]. Before his death, Demikhov was awarded the Pioneer Award by the International Society for Heart and Lung Transplantation for his innovations in the field.

Thanks to the advancements of John Gibbon, MD (Sept. 29, 1903–Feb. 5, 1973), the device known as the cardiopulmonary bypass machine (CPB) was realized [5, 7, 9]. Early in his career, Dr. Gibbon witnessed the death of a patient from a massive pulmonary embolism. While at Massachusetts General Hospital, he began engineering a machine that would take over the work of the heart and lungs during surgery [5, 7]. He continued his work after moving to the University of Pennsylvania in the 1930s. In collaboration with engineers at IBM, including engineer and IBM chairman Thomas Watson, and after many successful experiments in animal models, the first machine for human use was developed [5]. This model was a failure. A second machine was developed in Dr. Gibbon’s laboratory. This iteration minimized hemolysis and the formation of air bubbles and was operational (◘ Fig. 25.4).

The first successful use of the cardiopulmonary bypass machine (May 6, 1953) was on an 18-year-old patient with an atrial septal defect [5]. The patient survived a 26-min bypass “run” without complication. Unfortunately, subsequent operations with the CPB machine resulted in mortalities, and Dr. Gibbon then placed a moratorium on the CPB machine. Gibbon’s inventions earned him the Lasker Award in 1968. John Kirklin, MD (April 5, 1917–April 21, 2004), of the Mayo Clinic along with Richard A. DeWall, MD, and C. Walton Lillehei, MD (Oct. 23, 1918–July 5, 1999), of the University of Minnesota resumed Dr. Gibbon’s work and refined the CPB machine (◘ Fig. 25.5) [11]. Secondary to their work, cardiac surgery continued to mature in the late 1950s through 1960s.

In 1959, Drs. Henry Cass and Sir Russell Brock conducted several trials focused on canine heart transplantation. The technique left atrial cuffs instead of anastomosing the cava and pulmonary veins individually. These experiments met with limited success secondary to bleeding complications [5].

Norman E. Shumway , MD (Feb. 9, 1923–Feb. 10, 2006), completed medical school at Vanderbilt Medical School, his residency training at the University of Minnesota, and then his PhD in cardiovascular surgery in 1956 under Owen Wangenstein, MD (◘ Fig. 25.6) [5, 11]. During his research training, Dr. Shumway focused his efforts on total body hypothermia, pump oxygenators, prosthetic cardiovascular grafts, and arrhythmogenesis under the direction of F. John Lewis, MD (◘ Fig. 25.7), and Dr. Lillehei [11]. Shumway left Minnesota for California where he ultimately accepted a position at Stanford Medical Center in 1958.

At Stanford, Drs. Shumway and Richard R. Lower, MD (Aug. 15, 1929–May 17, 2008), were able to optimize surgical techniques and organ preservation, and they performed the first fully successful animal model orthotopic cardiac transplant in 1959 [5]. Drs. Shumway and Lower used preservation techniques that included topical hypothermia to 4 °C with saline for graft protection and recipient protection using cardiopulmonary bypass and systemic cooling to 30 °C. Surgical techniques using atrial cuffs, previously used by Demikhov, Cass, and Brock, helped limit ischemic times to 1 h [5]. Of eight animals, five survived 6–21 days, but they quickly died from myocardial failure due to cell infiltration and interstitial hemorrhage from lack of immunosuppression [12].

Observation on these animals suggest that, if the immunologic mechanism of the host were prevented from destroying the graft, in all likelihood it would continue to function adequately for the normal life span of the animal.

In 1961, Dr. Lower performed heart-lung transplant in canine models. Six recipients had spontaneous respirations post-implant and two were ambulatory [5]. The canine recipients died 5 days later and this was believed to be due to rejection. With continued research, it became apparent that immunologic responses were the limiting factor [12]. In 1965, Eugene Dong, MD, Dr. Lower, and Dr. Shumway found a relationship between EKG changes and rejection [5, 12]. They discovered that the EKG changes drastically improved with methylprednisolone and azathioprine, enabling one transplanted dog to survive 250 days [12].

James D. Hardy, MD (May 14, 1918–Feb. 19, 2003), tried to promote heart transplantation in humans by way of nonhuman donors. During this time period, brain death was not accepted as end of life for a possible donor; only cardiorespiratory arrest could be used to constitute death [5, 11]. This created a conundrum in the advancement of transplantation [5, 7].

…The donor heart presumably would be derived from a relatively young patient dying of brain damage and the recipient must be a patient dying of terminal myocardial failure… But how soon after “death” of the donor could the heart be removed?

Since we were not willing to stop the ventilator, we had concluded that a situation might arise in which the only heart available for transplantation would be that of a lower primate.

In 1964, the first human heart transplant using a nonhuman primate heart was undertaken. The first patient was a 68-year-old male with multiple medical problems, which led to a below-knee amputation, mechanical ventilation, vasopressors, and tracheostomy. At the time, there was no prospective human donor, but the dilemma with brain death again became a problem [5].

…for a homotransplant to succeed, the donor and the recipient must “die” at almost the same time; although this might occur, the chances that both simultaneously were very slim…Meanwhile, the condition of the prospective donor was not such that death appeared to be immediately imminent.

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