Heart transplantation

Editor(s)-in-Chief: C. Michael Gibson, M.S., M.D.; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [1]Ifrah Fatima, M.B.B.S[2]

Heart transplantation or cardiac transplantation, is a surgical transplant procedure performed on patients with end-stage heart failure or severe coronary artery disease when medical and device therapy have failed. The most common procedure is to take a working heart from a recently deceased organ donor (allograft) and implant it into the patient. The patient’s own heart may either be removed (orthotopic procedure) or, less commonly, left in to support the donor heart (heterotopic procedure).

Cardiac transplantation is reserved for patients with end-stage congestive heart failure despite all interventions. 1 year survival is 80%, and 5 year survival is 60%. Lifelong immunosuppressive therapy is used to prevent (or postpone) rejection, but increases the risk for opportunistic infections and malignancies.

The indications for heart transplantation include severe hemodynamic compromise due to heart failure which equires IV inotropic support to maintain adequate organ perfusion; a peak Vo2 <10 ml/kg/min; NYHA Class IV symptoms not amenable to any other intervention; or recurrence of symptomatic ventricular arrhythmias refractory to all therapeutic intervention.

The first heart transplant into a human occurred in 1964. The first human-to-human heart transplant was performed by Dr. Christian Barnard in 1967. Norman Shumway performed the first adult human to human heart transplant in the United States. Further developments in the field saw the emergence of standardization of recipient selection criteria, introduction of surveillance endocardial biopsy, distant donor heart procurement, and introduction of Cyclosporine A as an immunosuppressive regimen.

Cardiac Transplantation may be classified according to the surgical procedure performed into Orthotopic procedure and Heterotropic procedure.

The pathogenesis leading to a cardiac transplant involves the mechanisms leading up to heart failure. Heart failure leads to an inadequate output of the heart to meet the metabolic demands of the body. Features of chronic heart failure like biventricular hypertrophy, four-chamber dilatation, fibrotic scars, myofibrillar loss, sarcoplasmic vacuolation, interstitial fibrosis may be seen in the diseased heart. Post-transplantation changes indicating acute or chronic rejection may be seen. Non-rejection changes include coronary artery disease (eccentric), Quilty effect, interstitial fibrosis, nodular lymphocytic endomyocardial infiltrates, and posttransplant lymphoproliferative disorder in the transplanted heart.

The need for cardiac transplantation may result from advanced, irreversible heart failure with a severely limited life expectancy. Common causes include- Systolic Heart Failure with a Left Ventricular Ejection Fraction less than 35%, Ischemic Coronary Artery Disease with Refractory Angina, Intractable life-threatening Arrhythmias, Cardiomyopathies, and congenital Heart Disease.

About 4,000 heart transplants occur annually and about 2,200 per year in the United States. The leading indications for transplant in adult recipients is non-ischemic dilated cardiomyopathy. The median recipient age is 55 years. Death due to acute graft rejection is highest in the first 30 days and infectious complications are the leading cause in the first year. Post-transplant survival has improved over time.

The prognosis of the patient depends on a number of donor and recipient factors. If left untreated, patients develop acute graft rejection. Common complications of cardiac transplant include acute graft rejection, graft failure, infections, Cardiac allograft vasculopathy (CAV), malignancies, and late graft rejection.

There is no single diagnostic study of choice. A thorough evaluation should be done- including a physical examination and appropriate imaging to select the patients for a heart transplant. The indications and criteria should be fulfilled; the contraindications should be looked out for.

Patients requiring a cardiac transplant are generally with advanced, irreversible heart failure with a severely limited life expectancy. These patients would have failed medical and device therapy. Common indications include causes that led to this like- systolic heart failure with a left ventricular ejection fraction less than 35%, ischemic coronary artery disease with refractory angina, intractable life-threatening arrhythmias, cardiomyopathies, and congenital heart disease.

Contraindications to cardiac transplantation include any multisystem/systemic or life-shortening disease with a life expectancy of less than years, despite a heart transplant. Other factors that may be potential contraindications to be considered are- age, obesity, cancer, diabetes, renal dysfunction, peripheral vascular disease, infections, and substance abuse.

Criteria that should be met by the recipient to make cardiac transplantation suitable include evaluation with cardiopulmonary stress testing (peak oxygen consumption), heart failure prognosis scores- Seattle Heart Failure Model (SHFM), Heart Failure Survival Score (HFSS) and Index for Mortality Prediction After Cardiac Transplantation (IMPACT) score and diagnostic right heart catheterization.

Post cardiac transplantation, medical therapy with immunosuppressive drugs is essential to prevent both acute and chronic rejection. Immunosuppressive therapy is given in two phases- Induction therapy and Maintenance therapy. The drugs used include different combinations of drugs like IL-2 Receptor antagonists, Anti-thymocyte antibodies, calcineurin inhibitor, anti-metabolite, glucocorticoids, mammalian target of rapamycin [m-TOR] inhibitors, proliferation signal inhibitors and monoclonal Antibody OKT3.

Surgery is usually reserved for patients with advanced, irreversible heart failure with a severely limited life expectancy. Surgery is not the first-line treatment option for patients with heart failure. The mainstay of treatment for heart failure is medical/device therapy. The two types of operative procedures that can be performed are- orthotopic procedure and heterotropic procedure.

Many patients suffer from heart transplantation associated arrhythmias. These can be either tachyarrhythmias or bradyarrhythmias. These may arise due to presence of suture lines, graft manipulation, inflammatory changes, denervation, and rejection changes.

EKG shows accessory atrial activity due to some of the original sinus node still remains in addition to the donor sinus node after a cardiac transplant. For information on 2012 ACCF/AHA/HRS Focused Update of the 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities[3], click here.

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Editor(s)-in-Chief: C. Michael Gibson, M.S., M.D.; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [1]Ifrah Fatima, M.B.B.S[2]

The first heart transplant into a human occurred in 1964. The first human-to-human heart transplant was performed by Dr. Christian Barnard in 1967. Norman Shumway performed the first adult human to human heart transplant in the United States. Further developments in the field saw the emergence of standardization of recipient selection criteria, introduction of surveillance endocardial biopsy, distant donor heart procurement, and introduction of Cyclosporine A as an immunosuppressive regimen.

• 1964- The first heart transplant into a human occurred at the University of Mississippi Medical Center in Jackson, Mississippi when a team led by Dr. James Hardy transplanted a chimpanzee heart into a dying patient. ^[1]

• December 1967- Professor Christian Barnard performed the first human to human heart transplant at Groote Schuur Hospital, South Africa. The patient was a Louis Washkansky of Cape Town, South Africa, who lived for 18 days after the procedure before dying of pneumonia. The donor was Denise Darvall, who was rendered brain dead in a car accident. ^[2]

• December 6, 1967- Adrian Kantrowitz performed the world’s first pediatric heart transplant
• January 6, 1968- Norman Shumway performed the first adult human to human heart transplant in the United States at the Stanford University Hospital. ^[3]

Further developments in the field came in the form of:

• 1970 – Recipient selection criteria standardized

• 1973 – Surveillance endocardial biopsy

• 1977 – Distant donor heart procurement

• 1980 – Cyclosporine A

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ifrah Fatima, M.B.B.S[2]

Cardiac Transplantation may be classified according to the surgical procedure performed into Orthotopic procedure and Heterotropic Procedure.

Cardiac Transplantation may be classified according to the surgical procedure performed into:^[1]

• Orthotopic Transplant
• Heterotropic Transplant

In the orthotopic procedure a median sternotomy is done to expose the mediastinum. After opening the pericardium, the great vessels including the superior vena cava, inferior vena cava, pulmonary artery, pulmonary vein and aorta are dissected and cardiopulmonary bypass is attached. The diseased heart is taken out after transecting the great vessels and a part of the left atrium. The pulmonary veins are not transected; rather a circular portion of the left atrium containing the pulmonary veins is left in place. The donor heart is now fit onto the patient’s remaining left atrium and great vessels. The transplanted heart is started after slowly weaning the patient from cardiopulmonary bypass. The procedure is completed by closing the chest cavity.^{[2] [3]}

In the heterotopic procedure, the diseased heart is left in place and the donor heart is implanted. The donor heart is placed in a way to have the chambers and blood vessels of both hearts connected. This results in something to the effect of a ‘double heart’. In this way, the patient’s original heart can be given a chance to recover. Therefore, even if the donor heart fails, it is removed to allow the patient’s original heart to start working again. Heterotopic procedure is advantageous when the donor heart is not strong enough to function independently. This may be due to various reasons such as disproportionate body size of the patient and donor, the donor heart being weak, or pulmonary hypertension in the patient.^{[4] [2] [3]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ifrah Fatima, M.B.B.S[2]

The pathogenesis leading to a cardiac transplant involves the mechanisms leading up to heart failure. Heart failure leads to an inadequate output of the heart to meet the metabolic demands of the body. Features of chronic heart failure like biventricular hypertrophy, four-chamber dilatation, fibrotic scars, myofibrillar loss, sarcoplasmic vacuolation, interstitial fibrosis may be seen in the diseased heart. Post-transplantation changes indicating acute or chronic rejection may be seen. Non-rejection changes include coronary artery disease (eccentric), Quilty effect, interstitial fibrosis, nodular lymphocytic endomyocardial infiltrates, and posttransplant lymphoproliferative disorder in the transplanted heart.

Cardiac Transplantation is the treatment for patients with intractable heart failure, not amenable to medical and device therapy.

• Heart failure results when there is an inadequate output of the heart to meet the metabolic demands of the body. Heart failure can be caused by abnormal function of any part of the heart like the pericardium, the myocardium, the endocardium, the heart valves and the great vessels- the aorta and pulmonary artery.
• Heart failure is characterized by decreased cardiac output but not necessarily decreased ejection fraction.
• Symptoms of heart failure are due to a lack of both forward blood flow to the body, and backward flow into the lungs. The body tries to compensate for the low cardiac output by mechanisms that increase the preload and afterload. These mechanisms lead to exacerbation of the cardiac malfunction and symptoms associated with heart failure.

It is understood that heart failure is the end result of many causes- Common causes whose pathogenesis results in the need for cardiac transplantation may include:^[1]

• Systolic Heart Failure with a low Left Ventricular Ejection Fraction( <35%) may be caused by
  • Ischemic cardiomyopathy
  • Dilated cardiomyopathy
  • Valvular heart disease
  • Hypertensive heart disease
• Ischemic Coronary Artery Disease with Refractory Angina
• Long-standing Intractable life-threatening Arrhythmias
  • Ventricular arrhythmias
• Cardiomyopathies
  • Restrictive and Hypertrophic Cardiomyopathies
  • Non-dilated cardiomyopathies
• Congenital Heart Disease
  • Many congenital heart defects that are not amenable to surgery lead to New York Heart Association functional class IV Heart Failure

On gross pathology, features of chronic heart failure are seen-

• Biventricular hypertrophy
• Moderate to severe four-chamber dilatation are characteristic findings
• Remnant fibrotic scars from previous myocardial infarctions- transmural or subendocardial
• Mural thrombus– most commonly in the left ventricle but may be present in any chamber ^{[2] [3]}

On gross pathology, features of acute or chronic rejection may be seen, if the patient is not on adequate immunosuppressive therapy. ^[3]

• Hypertrophy of myocytes
• Myofibrillar loss
• Sarcoplasmic vacuolation
• Interstitial fibrosis
• Deposition of collagen, mostly in the subendocardial region.
• Variable degree of myocarditis^[3]

Features of mild acute rejection include ^[4]–

• Focal mononuclear cells infiltrate, without the involvement of adjacent myocytes.^[5]

Features of moderate acute rejection include-

• Dense collection of inflammatory cells, associated with involvement of adjacent myocytes.
• Eosinophils and also mononuclear cells are also seen in the infiltrate. ^[5]

Features of severe acute rejection additionally include-

• Hemorrhage
• Edema
• Vasculitis
• Neutrophilic infiltrate ^[2]

Features of chronic rejection include-

• Concentric intimal thickening
• Reservation of internal elastic lamina

• Coronary Artery Disease- Arteriosclerosis- concentric intimal thickening associated with endovasculitis. This is to be compared with ordinary atherosclerosis where lipids are deposited mainly in the endothelium and subendothelium in an eccentric pattern.
• Other changes like- ^[3]
  • Ischemic changes
  • Interstitial fibrosis
  • Mycoytes- hypertrophy, calcification
  • Nodular lymphocytic endomyocardial infiltrates- Seen with the use of Cyclosporin, known as Quilty effect ^[6]
  • Posttransplant lymphoproliferative disorder- Similar to large cell lymphoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ifrah Fatima, M.B.B.S[2]

The need for cardiac transplantation may result from advanced, irreversible heart failure with a severely limited life expectancy. Common causes include- Systolic Heart Failure with a Left Ventricular Ejection Fraction less than 35%, Ischemic Coronary Artery Disease with Refractory Angina, Intractable life-threatening Arrhythmias, Cardiomyopathies, and congenital Heart Disease.

• All the causes listed below are life-threatening as they lead to irreversible heart failure with very low ejection fraction and may cause sudden cardiac death if not optimized.

Common causes and indications that result in the need for cardiac transplantation may include:^{[1] [2] [3]}

• Systolic Heart Failure with a Left Ventricular Ejection Fraction less than 35%
  • Ischemic cardiomyopathy
  • Dilated cardiomyopathy
  • Valvular heart disease
  • Hypertensive heart disease
  • Etiologies which are excluded are amyloid, HIV, and cardiac sarcoma
• Ischemic Coronary Artery Disease with Refractory Angina
• Intractable life-threatening Arrhythmias
  • Ventricular arrhythmias which are not controlled by an implantable cardioverter-defibrillator
• Cardiomyopathies
  • Restrictive and Hypertrophic Cardiomyopathies with NYHA Class IV heart failure symptoms
  • Non-dilated cardiomyopathies
• Congenital Heart Disease
  • New York Heart Association functional class IV Heart Failure not amenable to surgery.

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Editor(s)-in-Chief: C. Michael Gibson, M.S., M.D.; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [1]Ifrah Fatima, M.B.B.S[2]

About 4,000 heart transplants occur annually and about 2,200 per year in the United States. The leading indications for transplant in adult recipients is non-ischemic dilated cardiomyopathy. The median recipient age is 55 years. Death due to acute graft rejection is highest in the first 30 days and infectious complications are the leading cause in the first year. Post-transplant survival has improved over time.

Reporting of transplant statistics to the Registry of the International Society for Heart and Lung Transplantation (ISHLT) is required in the US, but not other countries. According to The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult heart transplantation report — 2019: ^{[1] [2]}

• The incidence of heart transplants is approximately 4,000 heart transplants worldwide and about 2,200 per year in the United States, according to the ISHLT
• The volume of heart transplants reported to the ISHLT Registry is significantly higher owing to higher donor availability.
• In the year 1980s-1990s, the incidence of heart transplants saw a steady increase, but numbers have since stabilized because of the limited number of donors.

• The prevalence of heart transplants is approximately 4,000 heart transplants worldwide and about 2,200 per year in the United States, according to the ISHLT

• The survival rate of post-transplant patients was approximately 12.5 years, between 2002 and 2009. ^[1]
• The 1-year survival is 84.5% and 5-year survival is 72.5%. ^[3]
• Post-transplant survival has improved over time.
• Causes of death in the long term have not changed in recent years. Death due to acute graft rejection is highest in the first 30 days and infectious complications are the leading cause in the first year.

• The incidence of cardiac transplantation increases with age; median recipient age is 55 years.
• Median donor age in Europe has increased to 45 years and remains relatively stable in North America at 28 years and other countries at 31 years.

• There is no racial predilection to cardiac transplantation.

• males undergo cardiac transplant more commonly than women, according to the data from the ISHLT between 2009-2016. ^[4]

• The majority of heart transplant cases are reported in the United States.
• The International Society for Heart and Lung Transplantation (ISHLT) compiles the data of cardiac transplants and other involved statistics in the United States.
• Reporting of transplant statistics to the Registry of the International Society for Heart and Lung Transplantation (ISHLT) is required in the US, but not other countries.

• Reporting of transplant statistics to the Registry of the International Society for Heart and Lung Transplantation (ISHLT) is required in the US, but not other countries. ^[1]

• Reporting of transplant statistics to the Registry of the International Society for Heart and Lung Transplantation (ISHLT) is required in the US, but not other countries. ^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

There are no established risk factors that lead to cardiac transplantation. The prognosis of the patient post-transplantation depends on various donor and recipient factors.

Risk factors for poor outcome post-transplantation can be due to donor-specific characteristics, recipient-specific characteristics, and risk factors due to interactions between the donor and recipient.

Both the following factors are associated with an increased one-year mortality rate in the recipient.

• Advanced donor age ^[1]
• Prolonged ischemia time

• Use of total artificial heart as a bridge to transplant or a need for end-organ support in the form of mechanical ventilation or dialysis– associated with the greatest one-year mortality
• Best prognosis is seen if the indication for transplant is ischemic and nonischemic cardiomyopathy ^[2]

• Patients with a history of congenital heart disease, restrictive cardiomyopathy, and those undergoing retransplantation have a worse prognosis.
• Younger recipients (below age 55) have an advantage
• Pre-transplant serum creatinine and total bilirubin are linearly related to survival.

• Use of Amiodarone pretransplantation ^[3]
• Hypertension
• Hypercholesterolemia ^{[4] [5]}
• Diabetes
• Renal insufficiency
• Use of specific immunosuppressive regimen
• Elevated body mass index
• Tobacco use
• Obesity
• Early post-transplant complications
• Prior cardiac surgery
• Transplantation of a female heart into a male or female recipient ^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ifrah Fatima, M.B.B.S[2]

There is insufficient evidence to recommend routine screening for the need of cardiac transplantation. However, if a patient has indications for the need of a cardiac transplant, they should be thoroughly evaluated and screened

• There is insufficient evidence to recommend routine screening for the need of cardiac transplantation.
• According to the International Society for Heart and Lung Transplantation, screening of pre-transplant patients by the following tests is reccommended in patients with intractable heart failure– ^[1]
  • Cardiopulmonary stress testing
  • Heart Failure prognosis scores
  • Diagnostic Right Heart Catheterization
• These tests determine the appropriateness to proceed with a heart transplant. If these screening tests reveal contraindications or the ability to optimize the condition of the patient with medical and device therapy, the utility of cardiac transplant may be reconsidered.
• Other routine workups to detect contraindications are also done.

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Editor(s)-in-Chief: C. Michael Gibson, M.S., M.D.; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [1]Ifrah Fatima, M.B.B.S[2]

The prognosis of the patient depends on a number of donor and recipient factors. If left untreated, patients develop acute graft rejection. Common complications of cardiac transplant include acute graft rejection, graft failure, infections, Cardiac allograft vasculopathy (CAV), malignancies, and late graft rejection.

• Depending on the various factors of the donor and recipient at the time of transplant, the prognosis may vary.
• Prognosis is generally regarded as good. The 1-year survival is 84.5% and 5-year survival is 72.5%. ^[1]
• Post-transplant survival has improved over time.
• The median survival after adult heart transplants performed between 2002 and 2009 is 12.5 years, which extends to 14.8 years among 1-year survivors. ^[2]

The following are the factors determining prognosis–

Both the following factors are associated with an increased one-year mortality rate in the recipient.

• Advanced donor age ^[3]
• Prolonged ischemia time

• Use of total artificial heart as a bridge to transplant or a need for end-organ support in the form of mechanical ventilation or dialysis– associated with the greatest one-year mortality
• Best prognosis is seen if the indication for transplant is ischemic and nonischemic cardiomyopathy ^[4]

• Patients with a history of congenital heart disease, restrictive cardiomyopathy, and those undergoing retransplantation have a worse prognosis.
• Younger recipients (below age 55) have an advantage
• Pre-transplant serum creatinine and total bilirubin are linearly related to survival.

Some other risk factors are:

• Use of Amiodarone pretransplantation ^[5]
• Hypertension
• Hypercholesterolemia ^{[6] [7]}
• Diabetes
• Renal insufficiency
• Use of specific immunosuppressive regimen
• Elevated body mass index
• Tobacco use
• Obesity
• Early post-transplant complications
• Prior cardiac surgery
• Transplantation of a female heart into a male or female recipient. ^[8]

The following table outlines the common causes of death in post-cardiac transplant patients ^[9]

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