Cardiac Transplant

Heart failure affects 23 million people worldwide.^[1]There have been advancements in the drug treatment of heart failure but a number of patients will still progress to advanced heart failure. Heart transplantation provides symptomatic relief and restoration of quality of life to a small minority of patients.

Future alternatives to the current technology of cardiac allotransplantation may include xenotransplantation (transplantation of tissue and organs between different species) and/or non-biological replacement of the heart with mechanical devices.

Aetiology^[1]

Almost all adults presenting for transplant will have either a dilated idiopathic or ischaemic cardiomyopathy. Amongst children, dilated cardiomyopathy and congenital heart disease are the two most common indications.

Common indications

• Non-ischaemic cardiomyopathy (over 50%).
• Ischaemic cardiomyopathy.

Less common indications (1-3% of all cardiac transplants)

• Congenital heart disease.
• Valvular heart disease.
• Infiltrative conditions - eg, sarcoid, amyloid.

Indications

The general indication for cardiac transplantation is the New York Heart Association (NYHA) class III (symptoms with minimal exertion) or class IV (symptoms at rest) heart failure classification, where maximal medical therapy and/or cardiac resynchronisation therapy have failed.^[1]

More specific indications from the European Society of Cardiology are:^[2]

• Severe symptoms (NYHA class III or IV).
• Recurrent episodes of fluid overload or hypoperfusion.
• Cardiac dysfunction (ie left ventricular ejection fraction (LVEF) <30%, mitral inflow pattern suggests restriction or is pseudonormal, high ventricular filling pressures, severe impairment of functional capacity).
• One admission or more to hospital in the preceding six months.

Contra-indications^[2]

Absolute contra-indications

• Advanced irreversible chronic kidney disease.
• Advanced irreversible liver failure.
• Advanced irreversible pulmonary disease.
• Advanced irreversible pulmonary arterial hypertension.
• History of solid organ or haematological malignancy during previous five years.

Relative contra-indications

• Severe peripheral arterial disease.
• Severe cerebrovascular disease.
• Severe osteoporosis.
• Obesity (BMI >35 kg/m²) or cachexia.
• Active infection.
• Acute pulmonary embolus.
• Active peptic ulcer disease.
• Age over 70 years.
• Substance abuse (active or within the preceding six months).
• Psychiatric illness leading to instability.
• Diabetes with end organ damage.
• Any other comorbidity.
• Any issue which may lead to medication non-adherence.

Predictors of poorer survival

• Recipients: adverse factors include increasing age and high pulmonary vascular resistance.
• Donor heart: the age of the donor and the duration of graft ischaemia both have an impact on the quality of the donor heart.

Investigations^[1]

Exercise testing with measurement of maximum oxygen uptake is often used to make an objective assessment of the severity of cardiac dysfunction and therefore the necessity for cardiac transplant.

Exercise testing results can be combined with other factors into a scoring system for likely survival, allowing an objective evaluation for patient selection. Adverse factors include:

• Presence of coronary heart disease.
• Low LVEF.
• High resting heart rate.
• Intraventricular conduction delay (QRS duration >0.12 seconds).
• Low mean resting blood pressure.
• Low peak oxygen consumption.
• Low serum sodium.

Peri-operative management

Matching of recipient and donor

• The donor and recipient should be blood-group compatible.
• HLA matching is often not possible because of insufficient time. However, pre-existing antibodies to HLA antigens (caused by, for example, blood transfusion, pregnancy or a previous transplant) may cause immediate rejection, which is often fatal.

The operation

• The donor heart is anastomosed to the pulmonary artery and aorta. Separate caval anastomoses keep the donor right atrium intact.
• Assuming there are no complications, discharge from hospital is usually about two weeks following operation.

Complications

At five years after transplantation^[1]

• About a third of patients have abnormal renal function due to a combination of drug toxicity and pre-existing renal disease.
• A third have transplant coronary artery disease - see under 'Graft vasculopathy', below.
• A fifth have experienced malignancy.

Other complications
These include:

• Complications of anaesthesia and surgery: eg, bleeding, infection, drug reactions, deep vein thrombosis.
• Infection: particularly Epstein-Barr virus (EBV), which is a major cause of death in the first year after transplant. May require intravenous aciclovir and a reduction of the dose of immunosuppressant medication.
• Chronic immunosupression: causes increased risk of malignancy (mainly skin cancer or lymphoma).
• Hypertension: may occur in up to 70% of recipients. Angiotensin-converting enzyme (ACE) inhibitors are the first-choice antihypertensives. ACE inhibitors and calcium-channel blockers may benefit graft vasculopathy.
• Hyperlipidaemia: 50% of recipients have raised lipids after five years. All adult heart transplant patients should be treated with a statin.
• Osteoporosis: secondary to immunosuppressant drugs.
• Acute rejection: between 20-40% of patients have at least one episode of acute rejection. Acute rejection causes diastolic dysfunction. Presentation may be subtle but features may include fever, flu-like symptoms, a third heart sound, raised filling pressures or atrial flutter.
• Chronic rejection: causes accelerated coronary artery disease due to immune damage to the coronary arteries. This is the most common cause of late death after transplantation.

Immunosuppression and rejection

• Immunosuppression: the usual drugs used are ciclosporin A or tacrolimus, together with corticosteroids and one other agent. Drug toxicity is almost inevitable.
• Steroid treatment: starts with large intravenous doses of methylprednisolone, followed by oral prednisolone. Some patients can be weaned off steroids but a small dose of prednisolone enables lower doses of the other drugs to be used.
• The third drug used in 'standard triple-drug regimens' is usually azathioprine. Mycophenolate mofetil is an alternative but is more expensive and its role has not yet been fully evaluated.
• Monitoring rejection episodes:
  • The definitive investigation for detecting rejection is transvenous endomyocardial biopsy under local anaesthetic and radiological control. Echocardiography may have a role in children.
  • Biopsy is performed weekly for the first month, then at decreasing intervals over the first year.

Infection after transplantation

• Immunosuppression causes a high risk of infection, especially during the first few months after transplant.
• Within the first few weeks, infection is usually bacterial with common infections.
• Immunosuppression leads to a high risk of fungal infections, especially aspergillosis.
• Cytomegalovirus infection usually occurs in the first few months after transplantation. Prophylaxis with oral ganciclovir is used for patients at high risk. Intravenous ganciclovir is required for acute infection.
• Patients with fever require urgent investigations to identify the precise aetiology. Empirical antibiotics should be avoided unless for life-threatening infection.

Effects of chronic immunosuppression

• The risk of opportunistic infections reduces with time but can never be excluded.
• Malignant change in the skin exposed to sunlight is very common; precautions to reduce exposure to sunlight are essential.

Post-transplant lymphoproliferative disease^{[3, 4]}

• This can affect up to 10% of patients, most within the first year post-transplant.
• The clinical picture varies from infectious mononucleosis to a very malignant, multifocal lymphoma.
• Patients must be monitored for EBV seroconversion at presentation and then monthly. If the lymph node or tonsillar enlargement does not improve or worsens, biopsy should be carried out.
• In most cases reduction of immunosuppression causes the lymphoma to shrink. Chemotherapy may be required.

Graft vasculopathy

• Graft vasculopathy is the most common cause of death after the first year.
• Immunological damage to the coronary arteries may begin in the first few weeks after transplant. The process is accelerated with repeated rejection episodes, hyperlipidaemia, hypertension and the use of older donor hearts.
• Clinical presentation is subtle because of the denervation of the donor heart. It may lead to shortness of breath on exertion, silent myocardial infarction and sudden death. Detection is by angiography.
• Treatment with angioplasty or coronary stenting is often ineffective because of persisting small-vessel disease.

Prognosis^[5]

• Transplantation is effective in relieving the symptoms of heart failure. Over 90% of survivors are in NYHA class I or class II and report minimal limitation in activity.
• Heart transplantation has a high early mortality: 15-20% of recipients die within a year of the operation. 10-year survival is 50% and 20-year survival is 15%.