Heart Transplantation: The Present and Future

May 26, 2015   |  Pasala S. Ravichandran, MBBS, FACC

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History

The success story of heart transplantation is a testament to multi-disciplinary teamwork. Heart transplantation became a reality in the late 1960s after nearly a half of a century of research in surgical techniques, pathophysiology, and immunology by Drs. Richard Lower and Norman Shumway.1 Dr. Shumway is regarded as the father of heart transplantation. Dr. Christiaan Barnard, a student of Lower, performed the first heart transplantation in the laboratory on December 3, 1967. Dr. Adrian Kantrowitz performed the first pediatric transplant on Dec 6, 1967 in New York. He also laid the foundation for formulating the brain death criteria, which later came out of the Ad Hoc Committee of the Harvard Medical School. The early results were quite dismal, and many centers were forced to close their programs.2 In the late 1970s, survival improved to six years. Major advances in survival should be credited to Dr. Margaret Billingham for standardization of pathological diagnosis of rejection and later development of anti-rejection medicines.3 In 1983, the U.S. Food and Drug Administration (FDA) approved cyclosporin after its discovery by the Sandoz team.4 In October 1994, ventricular assist devices (VADs) were approved for supporting patients to transplant (bridge to transplantation [BTT]). Over 2,000 transplants are performed each year in the U.S., limited only by the number of organs available. In October 2014, Dr. Kumud Dhital of Australia transplanted a heart that was resuscitated after cardiac death of the donor, opening a new door to increasing the number of organs.

Team Approach to Treating Patients With Advanced Heart Failure

Heart failure management sets an example for how a complex disease should be approached. The following characteristics of patient-centered multidisciplinary teams are similar to cancer treatment approach:5

  1. Treatment from a professional with specialist knowledge and skills in heart failure.
  2. Availability of the opportunity for patients to enter into high-quality/randomized clinical trials.
  3. Patients are assessed and offered the level of information and support they need to manage and cope with their condition.
  4. Addressing vigilant medical follow-up, compliance issues, exercise programs, and daily monitoring.
  5. Continuity of care with real-time communication between different caregivers and health care providers at the level of primary, secondary, and tertiary care.
  6. Adherence to national and international guidelines.
  7. Collection of all scientific data for audit and research with the purpose of benefitting the patient population.
  8. Promotion of a good working relationship between staff, thereby enhancing job satisfaction and quality of life. Alignment of staff to the success of the service line.
  9. Opportunities for educational development of team members. Frequent recognition and reward for all levels of success.
  10. Optimization of resources and best utilization of time.
  11. Consideration of cost-effectiveness of care.

Heart failure consumes about 2.5% of the heath care budget, and a large number of patients admitted to hospitals for other reasons have heart failure. The purpose of the team approach is to prevent any further deterioration.6-9 The patients referred for heart transplantation are in stage D heart failure and suffer from severe symptoms in spite of guideline-directed medical treatment (GDMT).10 The European Society of Cardiology (ESC) definition of advanced heart failure and the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles are used to guide further stratification and selection of patients. The seven INTERMACS levels are an attempt to simplify the understanding of the severity of heart failure and decision making for circulatory support, which has become an important component before heart transplantation. Level 1 patients are in a life-threatening stage requiring urgent intervention, and level 5 patients are mainly housebound due to heart failure, possibly requiring support electively. Patients at levels 2-4 need constant monitoring and intervention in a timely manner. Patients at levels 6-7 are medically managed reasonably well to stay away from mechanical intervention.11 The listing criteria are based on cardiopulmonary exercise testing, heart failure prognosis scores, risk stratification, and frequent reassessments.12 Right heart catheterization is performed for listing and assessing annually until transplantation. Assessment of comorbidities and psychosocial evaluation are integral components of evaluation.

Care of Heart Transplant Patients After Surgery

Short- and long-term management of cardiac transplant patients involves cardiac support, as well as monitoring and treatment of rejection, infection, and malignancies. Organ rejection presents itself as hyperacute, acute cellular or acute antibody-mediated rejection. Hyperacute rejection occurs within minutes to hours due to binding of preformed antibodies to donor antigens leading to complement fixation in vessels and tissue death. Acute cellular rejection is more common in the first six months occurring in 20-40%. It is T cell-mediated against the donor's human leucocyte antigen (HLA). Acute antibody-mediated rejection occurs in about 10% usually due to antibodies driven by T cells to donor vascular antigens. This leads to B cell activation and production of plasma cells. It is difficult to diagnose but usually associated with detection of immunoglobulins, complement fragments, CD 68 positive cells, and de novo anti-HLA antibodies. Surveillance endomyocardial biopsies are essential in the first year to detect rejection at the subclinical level before the development of cardiac dysfunction.4 Infants and children have lower rejection rates while adolescents have higher rates. Any symptoms after heart transplant need to be assumed to be due to rejection. There are several adjunct noninvasive measures under investigation based on electrophysiology, magnetic resonance imaging, biochemical markers, and gene expression profiling.

The introduction of mycophenolate mofetil (MMF), tacrolimus, cyclosporine microemulsion, sirolimus, rapamycin protein inhibitors, new generation monoclonal antibodies ( anti-interleukin-2 receptor antagonists, daclizumab, basilix-imab, alemtuzumab), OKT3, and the depleting polyclonal biologic thymoglobulin has significantly increased the ability of physicians to fight rejection.13 However, there is a price to pay in the form of increased infections and malignancies. The problem of intimal and smooth muscle proliferation leading to graft vessel disease remains unresolved. Recent advances in therapy have been minimal except for drug minimization protocols leading to reduction of corticosteroid and calcineurin inhibitors. At the same time, the advances in the management of allosensitization are noteworthy. The crossmatch prevents transplanting in the presence of donor-specific antibodies. Panel reactive antibody (PRA) screening is done in all heart transplant candidates, and further evaluation is needed if PRA levels are elevated above 10%. The factors involved leading to sensitization are homograft use in congenital surgery, female sex, prior pregnancies, black race, VAD surface exposure, retransplantation, perioperative blood products usage, and infections. It is diagnosed by measuring PRAs. PRA levels greater than 10% are treated, and aggressive desensitization with plasmapheresis, intravenous immunoglobulin (IVIG), and rituximab is associated with significantly improved survival. IVIG is used to neutralize preformed antibodies before and after transplantation. The effectiveness is variable. Plasmapheresis is fast, short-lived, and can be done immediately before transplantation. Rituximab (anti-CD20) is frequently used and is effective in the long term. Immunoabsorbtion and spelenectomy are rarely used.14-17 The rate of infection is very high with these therapies. Because of their immature immune systems, infants can have ABO incompatible organs. The limit of isohemagglutinins titer that makes this possible is not determined.18,19

Outcomes of Heart Transplantation

One-year survival after heart transplantation exceeds 80%, with 10-year survival approaching 60% and 20-year survival at about 20%. Survival after retransplantation is about 10% lower.20 Ten-year survival is highest in patients with adult congenital heart disease, followed by patients with cardiomyopathy, valvular heart disease, ischemia, and retransplantation. Survival also depends on age, gender, and other comorbid factors of recipients and donors. Major causes of early death are primary graft failure; rejection; infection; technical followed later by allograft vasculopathy; lymphomas; other malignancies; and renal, pulmonary, cerebrovascular, and multi-system failures.

The Future of Heart Transplantation
Treatment of Heart Failure

Shared decision making between caregivers and patients leads to the development of quality measures based on patient education and experience. This will involve regular monitoring and treatment based on guidelines. The patients are made aware of the different choices of both medical and device treatments. Future research in areas related to shared decision making, effective communication training, decision support interventions, group visits, health-related quality-of-life measures, and caregiver burden, needs, and outcomes.10

Improving Post-Transplant Survival

There have been some recent advances in immunosuppressive therapy. Future management will be directed towards minimization of steroids and calcineurin inhibitors by effective blockade of the co-stimulatory pathway. Major advances are needed towards noninvasive rejection monitoring, especially in children. Improving survival by reducing the incidence of atherosclerotic and renal disease.

Reducing the Number of Recipients

The majority of the ambulatory patients in heart failure do not come for heart transplantation in the recent era. They are patients either hospitalized or supported by mechanical means. Future studies will involve mechanical circulatory support (MCS) with smaller and more durable devices. Some of the very small devices can be implanted to provide partial cardiac support during late stage C or early stage D, leading to reversal of neurohormonal changes in heart failure and long-term symptomatic relief equivalent to heart transplantation and sometimes heart recovery.

Increasing Donors

Significant improvement has occurred due to better education and aggressive management of marginal donors, leading to an increase in available hearts.21 Changes in the consent process based on "required response" from people related to their willingness to donate will make the consent process easier. Efforts to resuscitate and use hearts from non-heart beating donors are underway.

Reducing Pre- and Post-Transplant Mortality Using MCS

Earlier MCS before the occurrence of multi-organ failure has resulted in improved survival already. Studies are needed using support in patients who are less sick in the future.

References

  1. Kirklin jk, Mehra M, West LJ. History of International Heart and Lung Transplantation. ISHLT Monograph Series, vol. 4. Elsevier; 2010.
  2. Thompson T. The tragic record of heart transplants. The year they changed hearts. Life Magazine 1971:56-70.
  3. Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 2005;24:1710-20.
  4. Heusler K, Pletscher A. The controversial early history of cyclosporine. Swiss Med Wkly 2001;131:299-302.
  5. National Cancer Action Team (NHS). The Characteristics of an Effective Multidisciplinary Team (MDT) (NHS website). 2010. Available at: http://www.nhsiq.nhs.uk/media/2444560/ncatmdtcharacteristics.pdf. Accessed 5/3/15.
  6. Jaarsma T. Inter-Professional team approach to patients with heart failure. Heart 2005;91:832-8.
  7. National Heart Foundation of Australia. Multidisciplinary care of people with chronic heart failure. Principles and recommendations for best practice (Queensland Government website). 2010. Available at: http://www.health.qld.gov.au/heart_failure/pdf/HF_MDC_CHF.pdf. Accessed 5/3/15.
  8. McAlister FA, Stewart S, Ferrua S, et al. Multidisciplinary strategies for the management of heart failure patients at high risk for admission. J Am Coll Cardiol 2004;44:810-9.
  9. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;128:e240-329.
  10. Allen L, Stevenson LW, Grady K, et al. Decision making in advanced heart failure: a scientific statement from the American Heart Association. Circulation 2012;125:1928-52.
  11. Frazier OH, Kirklin JK. Mechanical Circulatory Support. ISHLT Monograph Series, vol 1. Elsevier; 2006.
  12. Mehra MR, Kobashigawa J, Sterling R, et al. Listing criteria for heart transplantation: international Society for Heart and Lung transplantation Guidelines for the Care of Cardiac Transplant Candidates--2006. J Heart Lung Transplant 2006;25:1024-42.
  13. Tait BD, Susal C, Gabel HM, et al. Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation 2013;95:19-47.
  14. Vincenti F. Immunosuppression minimization: current and future trends in transplant immunosuppression. J Am Soc Nephrol 2003;14:1940-8.
  15. Alba AC, Tinckam K, Foroutan F, et al. Factors associated with anti-human leukocyte antigen antibodies in patients supported with continuous-flow devices and effect on probability of transplant and post transplant outcomes. J Heart Lung Transplant 2015;34:685-92.
  16. Asante-Korang A, Amankwah EK, Lopez-Cepero M, et al. Outcomes in highly sensitized pediatric heart transplant patients using current management strategies. J Heart lung Transplant 2015;34:175-81.
  17. Schaffer JM, Singh S, Reitz B, et al. Heart transplant survival is improved after a reduction in panel reactive antibody activity. J Thorac Cardiovasc Surg 2013;145:555-65.
  18. Thrush PT, Hoffman TM. Pediatric heart transplantation-indications and outcomes in the current era. J Thorac Dis 2014;6:1080-96.
  19. West LJ, Pollock-Barziv SM, Dipchand AL, et al: ABO-Incompatible heart transplantation in infants. N Engl J Med 2001;344:793-800.
  20. Alraies MC, Eckman P. Adult heart transplantation: indications and outcomes. J Thorac Dis 2014;6:1120-8.
  21. Kobashigawa JA, Johnson M, Rogers J, et al. Report from a forum on US heart allocation policy. Am J Transplant 2015;15:55-63.

Keywords: Adolescent, Adrenal Cortex Hormones, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antibodies, Monoclonal, Murine-Derived, Antilymphocyte Serum, Biomarkers, Biopsy, Brain Death, Cardiac Catheterization, Cardiomyopathies, Caregivers, Child, Comorbidity, Complement System Proteins, Continuity of Patient Care, Cost of Illness, Cyclosporine, Decision Making, Electrophysiology, Follow-Up Studies, Gene Expression Profiling, Heart Diseases, Heart Failure, Heart Transplantation, Heart Valve Diseases, Heart-Assist Devices, Immunoglobulin G, Immunoglobulins, Intravenous, Incidence, Job Satisfaction, Lymphoma, Magnetic Resonance Imaging, Muromonab-CD3, Muscle, Smooth, Mycophenolic Acid, Neoplasms, Plasma Cells, Plasmapheresis, Pregnancy, Prognosis, Quality of Life, Receptors, Interleukin-2, Registries, Reoperation, Sirolimus, T-Lymphocytes, Tacrolimus, Tertiary Healthcare


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