Cardiac transplant

What is a cardiac transplant?

Heart transplantation remains the gold standard for the treatment of advanced heart failure in the absence of contraindications.

Organ donor shortage remains the main limitation to heart transplantation. Thus, the donor heart criteria have now been extended to allow an increased upper limit of the donor age, particularly in Europe. However, careful recipient selection is needed, based on pre-transplant and post-transplant life expectancy (both are influenced by pre-operative status and comorbidities).

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.

See also the articles on Heart Failure Diagnosis and Investigation and Heart Failure Management.

Indications²

Advanced heart failure. The criteria for definition of advanced heart failure are as follows (all the following criteria must be present despite optimal medical treatment):

• Severe and persistent symptoms of heart failure: New York Heart Association (NYHA) class III (symptoms with minimal exertion) or class IV (symptoms at rest).

• Severe cardiac dysfunction defined by at least one of the following:

  • Left ventricular ejection fraction of or below 30%.

  • Isolated right ventricular failure (eg, arrhythmogenic right ventricular cardiomyopathy).

  • Non-operable severe valve abnormalities.

  • Non-operable severe congenital abnormalities.

  • Persistently high (or increasing) BNP or NT-proBNP values and severe left ventricular diastolic dysfunction or structural abnormalities.

• Episodes of pulmonary or systemic congestion requiring high-dose IV diuretics (or diuretic combinations) or episodes of low output requiring inotropes or vasoactive drugs or malignant arrhythmias causing more than one unplanned visit or hospitalisation in the last 12 months.

• Severe impairment of exercise capacity with inability to exercise or low 6-minute walk distance (less than 300 m) or peak oxygen consumption below 12 mL/kg/min or below 50% predicted value, estimated to be of cardiac origin.

No other therapeutic option, except for left ventricular assist device as bridge to transplantation.

Contra-indications²

• Active infection.

• Severe peripheral arterial or cerebrovascular disease.

• Pharmacologic irreversible pulmonary hypertension (left ventricular assist device should be considered to reverse elevated pulmonary vascular resistance with subsequent re-evaluation to establish candidacy).

• Malignancy with poor prognosis.

• Irreversible liver dysfunction (cirrhosis) or irreversible renal dysfunction (eg, creatinine clearance below 30 mL/min/1.73 m2 ). Combined heart-liver or heart-kidney transplant may be considered.

• Systemic disease with multiorgan involvement.

• Other serious comorbidity with poor prognosis.

• Pre-transplant body mass index above 35 kg/m² (weight loss is recommended to achieve a BMI below 35 kg/m²).

• Current alcohol or drug abuse.

• Psychological instability that jeopardises proper follow-up and intensive therapeutic regime after heart transplantation.

• Insufficient social supports to achieve compliant care in the outpatient setting.

Active infection is a relative contraindication to transplant but in some cases of infected left ventricular assist devices it may actually be an indication.

Elderly age is not an absolute contraindication. Although patients aged under 65 years might be more appropriate candidates due to their overall life expectancy, most programmes accept patients up to 70 years of age, and biological age as well as chronological age must be taken into account. Surgical complexity (previous sternotomies, mediastinal radiation, adult congenital heart disease) should also be considered.

The decision pathway to transplantation or left ventricular assist device is never straightforward and is unique to each patient. Eligibility for each option may change according to the particular conditions of each patient, which may also change over time. Other factors, not related to the patient, such as time on the heart transplant waiting list, the centre’s surgical experience, and resources, can also influence decision making.

Predictors of poorer survival³

Recipients' adverse factors include increasing age and high pulmonary vascular resistance. Factors of the donor heart include the age of the donor and longer duration of graft ischaemia. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation report in 2020 focused on deceased donor characteristics and found:

One-year survival:

• Older donor age is associated with reduced post-transplant survival, and most of this effect is seen within the first month after transplantation.

• Receipt of a heart from a donor with a history of smoking (more 20 pack-years) was associated with 3% lower 1-year survival, whereas receipt of a heart from a donor with a history of alcohol abuse (defined as 2 or more alcoholic drinks per day) was not associated with increased mortality. Donor cocaine use did not have a significant impact on recipient 1-year survival, whereas the use of other drugs (non-intravenous street drugs such as crack, marijuana or prescription narcotics, sedatives, hypnotics, or stimulants) was associated with marginally higher recipient 1-year survival. This is likely a confounded effect related to the younger age of donors who abused other drugs and who probably had fewer medical comorbidities than older donors who did not abuse street drugs.

• Recipients of hearts from donors with diabetes and hypertension had significantly lower 1-year survival than recipients of hearts from donors without these medical conditions. However, these differences were often quite small.

• Recipients of younger donor hearts have improved survival relative to recipients of older donor hearts, regardless of whether ischaemic time was less or more than 4 hours.

• Recipients of donor hearts with both left ventricular ejection fraction below 50% and graft ischaemic time 4 hours or more have worse survival.

5-year survival:

• Younger donor age is associated with improved 5-year conditional survival.

• Donor diabetes and hypertension continue to be associated with reduced recipient 5-year survival.

• Donor left ventricular dysfunction (left ventricular ejection fraction below 50%) has a greater impact on recipient 5-year survival than on recipient 1-year survival.

• Donor smoking history continues to be associated with reduced recipient 5-year survival. Donor alcohol use is associated with slightly increased 5-year mortality. Donor cocaine use is not associated with 5-year survival, and donor history of other drug use (non-intravenous street drugs) is not associated with 5-year survival.

• There was no difference in 5-year conditional survival between donors with ischaemic time less than 4 hours and donors with ischaemic time 4 hours or longer, which suggests that the detrimental effect of prolonged ischaemic time on recipient survival is seen mainly within the first year after transplantation.

Investigations¹

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 left ventricular ejection fraction (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.

Identification of potential organ donors⁴

In general, potential organ donors are patients mechanically ventilated in a state of brain death (the majority), or in a state of circulatory death.

The first stage in evaluating potential donors includes confirmation of brain death or establishment of circulatory death, as well as verification of consent to the donation. The main factors that are considered to confirm donors’ suitability include:

• • • Age: age under 45 years is recommended for heart donors. Donors older than 45 years may be considered after careful screening for the presence of significant coronary artery disease and if graft ischaemia times more than 4 hours is expected. Older donors can be considered for older recipients or highly sensitised recipients with negative crossmatch.

    • Size: assignment of hearts from female donors to male recipients can be performed safely, especially in the absence of pulmonary hypertension or when the predicted heart mass value in the recipient is within 20% to 30%.

    • Other donor factors will include haemodynamic status, metabolism status, systolic function, blood Group and anti-human leukocyte antigen (HLA) compatibility, as well as comorbidities:

    • Left ventricular hypertrophy should be detected by echocardiography in all donors.

    • Coronary artery disease should be researched by coronary angiography in patients with age under 45 years, diabetes, hypertension, obesity, hyperlipidaemia, or tobacco and/or cocaine/methamphetamine use.

    • The heart of donors with a history of tobacco, cocaine, and amphetamine abuse can be safely used if the systolic function is normal, maximal wall thickness is less than 14 mm, and coronary angiography is normal.

Complications of a cardiac transplant²

Apart from primary graft dysfunction, the main challenges after heart transplantation relate to either the efficacy or side effects of immunosuppression (eg, rejection, infection, cardiac allograft vasculopathy, late graft dysfunction, malignancy, renal failure, hypertension, diabetes mellitus).

At five years after transplantation¹

• • • 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 immunosuppression: 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^{5 6}

• • • 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.

Prognosis²

• • Post-transplant 1-year survival is around 90% with a median survival of 12.5 years.

  • Transplantation significantly improves quality of life and functional status, although, for unclear reasons, the percentage of patients returning to work is lower than expected.