Management of Cardiac Transplant Patients in the Emergency Department

Context

Cardiac transplantation is an effective treatment for end stage heart failure. Five year survival is around 75% [1]. There are a variety of health problems to which these patients are susceptible and which can lead to presentation to the emergency department (ED). It is also important to have an understanding of the issues surrounding the transplanted organ when assessing the patient for an apparently unrelated problem.

Anatomy and Pathophysiology

(i) Transplant techniques:

Orthotopic heart transplant is when the donor heart replaces the native heart. The alternative is heterotopic transplant (Fig 1) in which the donor heart is placed beside the native heart, which continues to function. The first human heart transplant was performed by Christiaan Barnard in 1967 using the heterotopic technique. This is now seldom used, but may be appropriate in cases of severe recipient pulmonary hypertension, or a significant size mismatch between a small donor and a large recipient [2].

The original orthotopic procedure involved grafting the donor right atrium directly on to the recipient right atrium (Fig 2). The more recent bicaval technique (Fig 3) involves the superior vena cava and inferior vena cava being attached separately [3]. This helps to preserve normal atrial structure and function.

Fig 1: Heterotopic heart transplant

Fig 2: Biatrial orthotopic heart transplant

Fig 3: Bicaval orthotopic heart transplant

(ii) Graft rejection:

Transplant patients are at risk of graft rejection. This can either be hyperacute (within hours), acute (weeks to months) or chronic (months to years). Acute rejection is further divided into cellular or humoral:

• Acute cellular rejection is T cell mediated. It is mostly diagnosed on surveillance endomyocardial biopsy in patients who are asymptomatic
• Acute humoral rejection is antibody mediated and is characterised by a high incidence of haemodynamic compromise, graft loss and death

(iii) Cardiac transplant vasculopathy:

The major factor limiting long term survival for heart transplant recipients is their tendency to develop coronary artery disease. This differs from conventional coronary disease. Native coronary disease tends to be focal and non-concentric and often affects the proximal vessel. Graft coronary disease is diffuse and concentric and affects mid and distal vessels. It is an aggressive disease process and affects 32% of recipients at five years [4].

Clinical Presentation

It is possible for heart transplant patients to present to the ED with vague and non-specific complaints when in fact they have a life threatening illness. It is important to maintain a high index of suspicion for graft rejection, infection and graft vasculopathy, complications directly associated with cardiac transplantation or the drugs associated with transplantation.

Patients with transplanted hearts can also present with more conventional forms of cardiac disease such as heart failure, arrhythmias and ischaemia which will require assessment and appropriate ED-based intervention, some features of which have specific issues related to a transplanted heart.

(i) Rejection:

This most commonly occurs in the first year after transplant. Often the diagnosis is made on routine biopsy. The patient may look and feel well. When they become ill, they present with signs and symptoms of heart failure.

(ii) Problems related to immunosuppression:

Transplant patients are immunosuppressed. They are therefore susceptible to a range of organisms including ones which are predominantly encountered in the immunocompromised. These include candida, cytomegalovirus (CMV image) and pneumocystis jirovecii pneumonia (PCP). CMV in particular is common following transplantation. It may present with constitutional symptoms, hepatitis, nephritis, pneumonitis or low platelets. The patient may not be overtly septic. They may be febrile, but this is not essential to the diagnosis of infection.

Pitfall

Immunosupressed patients may have an opportunistic infection without an associated fever.

The medications given to suppress the immune system post-transplantation can cause a variety of adverse effects in addition to increased susceptibility to infection:

• Steroids can cause Cushings syndrome which is associated with type II diabetes mellitus and hypertension
• Cyclosporin may be toxic to the liver and kidneys. It can cause hypertension. It may lead to elevated potassium, lipids or glucose. It causes hirsutism
• Azathioprine is hepatotoxic. It can cause falls in haemoglobin, white cell count and platelet count. It is associated with an increased risk of malignancy
• Tacrolimus is toxic to the liver and kidneys. It may lower platelet count and raise potassium or lipids

Some drugs can increase the levels of immunosuppressants, increasing the risk of toxic effects. Alcohol, clarithromycin and calcium channel blockers can have this effect.

Other medications can lower immunosuppressant drug levels making them ineffective. Phenytoin and rifampicin are examples.

Learning Bite

It is important to exercise caution when changing the treatment regime of a transplant patient. Liaison with the transplant team is recommended.

(iii) Ischaemia:

Graft vasculopathy should be considered in patients presenting several years after a heart transplant. Ischaemia usually occurs without pain because the graft heart is denervated. The patient may present with heart failure, an arrhythmia or sudden death. The presentation may be non-specific with features such as breathlessness, sweating and nausea.

Pitfall

Cardiac ischaemia usually occurs without pain because the graft heart is denervated.

(iv) Malignancy:

An increased risk of malignancy is another side effect of immunosuppression [6]. Incidence is 100 times greater in heart transplant patients than in the general population. Lymphoproliferative disorder is common, often with extranodal involvement. Diagnosis may be made on biopsy of the lymph node, bone marrow or endocardium.

(v) Pericardial disease:

A moderate or large pericardial effusion is common after transplantation. It is rarely sufficient to cause tamponade. Because transplant patients are at increased risk of infection and malignancy, one should have a low threshold for a diagnostic pericardiocentesis. Constrictive pericarditis may ultimately arise due to the effusion or any local infection, inflammation or haematoma. Post pericardiotomy syndrome may lead to constriction.

(i) History

Important features of history:

• Date of transplant
• Time course of symptoms
• Any known episodes of rejection
• Details of anti-rejection drugs and patients compliance
• Any history to suggest sepsis: general features such as fever, or symptoms of a specific focus such as cough/ expectoration
• Cardiac symptoms (which might suggest graft failure due to rejection or vasculopathy): breathlessness/paroxysmal nocturnal dyspnea (PND)/orthopnoea; dizziness or syncope; palpitations

(ii) Examination

Important clinical signs:

• Tachycardia may be normal post-transplant
• Bradycardia common soon after surgery
• Blood pressure often high in transplant patients; may be low in sepsis or graft failure
• Lung fields crepitations in heart failure or pneumonia
• Ankle oedema in right heart failure
• Temperature elevated in sepsis, but this is not a reliable marker for infection

The ECG after cardiac transplantation

Assess for the following on ECG after cardiac transplantation [5-7]:

(i) Sinus tachycardia

This may be normal in a transplanted heart, arising as a consequence of autonomic denervation. The heart rate tends to fall over time. A persistently rapid heart rate may lead to tachycardia induced cardiomyopathy. Alternatively, a fast heart rate may be a manifestation of a failing heart.

(ii) Recipient p waves

P waves on the ECG may arise from the atrial remnant of the recipient. They are dissociated from the graft QRS complexes. If they occur in the context of a donor bradycardia, they may lead to heart block being diagnosed incorrectly.

(iii) Right bundle branch block

This is a common finding and may reflect elevated right heart pressure or right ventricular dysfunction.

(iv) Atrial premature beats (APBs)

APBs are a common finding in transplant ECGs. They may become less frequent over time. An increase in frequency may be associated with graft rejection.

(v) Atrial flutter (AF) or fibrillation

Approximately 18% of transplant patients develop AF or flutter. These rhythm disturbances become more common when rejection occurs. AF may be treated with amiodarone or cardioversion. Digoxin is ineffective. Caution must be exercised in prescribing beta blockers because the graft uses circulating catecholamines to increase cardiac output. Therefore whilst they are effective for achieving rate control, the patient must be observed carefully for signs of clinical deterioration. AF may respond to overdrive pacing or cardioversion. Ablation may also be considered.

Supraventricular tachycardias

A variety of supraventricular arrhythmias can occur in orthotopic heart transplant recipients, including atrioventricular (AV) reentrant tachycardia involving a concealed AV bypass tract , Wolff-Parkinson-White syndrome, and sustained atrial tachycardias. Radiofrequency catheter ablation has been performed in many of these patients with success.

Adenosine should not be used to try to elucidate the mechanism of supraventricular tachyarrhythmias since it can result in transient, but significant, bradyarrhythmias.

Pitfall

Exercise caution using beta blockers in patients with transplants because these patients use circulating catecholamines to increase cardiac output.

(vi) Ventricular arrhythmias

These are rare in the early period following transplant. They may occur following the use of antiarrhythmics for atrial rhythm disturbances. In the late period after transplant, VF and VT may be caused by graft coronary disease. This may present as sudden cardiac death.

(vii) Sinus node dysfunction

Sinus bradycardia is common immediately after transplant. Sinus node disease is the commonest cause of bradyarrhythmia in the transplanted heart. This may be due to perioperative ischaemia or surgical trauma affecting the sinus node. It tends to improve over time. Permanent pacemakers can be used to treat symptomatic patients. Only about a third of patients receiving a pacemaker will actually pace long term. An isoprenaline infusion may improve the rate whilst pacing is arranged. Atropine is ineffective in transplant bradyarrhythmias because the heart is denervated.

(viii) Atrioventricular (AV) block

This is less common than sinus node dysfunction following transplantation. It must be distinguished from recipient p waves giving the appearance of heart block. It is more common in late onset bradyarrhythmias and there may be underlying rejection or graft vasculopathy. A patient with AV block should therefore be further investigated with angiography and biopsy. If the patient is haemodynamically compromised, a permanent pacemaker should be inserted.

Learning Bite

The rhythm-related consequences of denervation of the graft heart are (a) a persistent tachycardia, (b) reliance on circulating catecholamines to increase heart rate and (c) atropine is ineffective in treating transplant bradyarrhythmias.

(ix) Ischaemic changes

Ischaemia in the transplanted heart may produce conventional ST segment and T wave changes. If a patient is found to have frank ST segment elevation, a working diagnosis of infarction should be made. It may be difficult to establish a time course for this in the likely absence of pain. ST segment depression and T wave inversion should similarly raise the suspicion of ischaemia. However, the ECG in transplant patients must be interpreted with caution. There are case reports of pseudo-infarct ECGs of transplant patients who were subsequently found to have neither regional wall motion abnormality on echo nor obstructive coronary disease at angiography [8]. It has been speculated that myocardial oedema and reperfusion injury following surgery may be one cause of such ECG changes. The ECG may normalise with time and this can be associated with a reduction in left ventricular (LV) wall thickness as oedema resolves.

Pitfall

beware pseudo-infarction in transplant patients where ST segment elevation may represent myocardial oedema or surgical injury rather than ischaemia

Blood tests: U&Es, FBC, CRP, troponin

Routine blood tests will include markers for infection such as white cell count and CRP. CRP is also elevated with graft rejection and graft vasculopathy. U&Es may demonstrate renal impairment associated with a deteriorating heart. Troponin has not been found to be reliable in evaluating graft rejection. It may be useful in identifying patients with graft vasculopathy. An elevated troponin, ideally relative to a previous baseline, suggests myocardial injury. Coronary artery disease and rejection should be considered as causes. Drug levels for immunosuppressants may be helpful if poor compliance is suspected.

Blood and urine cultures

Transplant patients are immunosuppressed, and one should have a low threshold for a septic screen including blood cultures and MSU.

Chest x-ray (CXR)

There will be sternotomy sutures from a previous thoracotomy. If there is LV dysfunction, the CXR may demonstrate cardiomegaly and pulmonary oedema. It may also show evidence of infection or malignant disease.

Echocardiography

This will be abnormal simply because the heart is transplanted. Common findings include a dilated left atrium, abnormal septal motion and valvular regurgitation. Diastolic dysfunction on tissue Doppler may be suggestive of acute rejection. Graft vasculopathy may cause regional wall motion abnormality.

Endomyocardial biopsy

This is the diagnostic test for graft rejection. Tissue is obtained from the right ventricular (RV) septum using a percutaneous transvenous approach. The test may also show evidence of inflammation, infiltration or ischaemia.

Serological tests

These should be performed for opportunistic infections, such as CMV.

Transplant patients may seem reasonably well despite having a sinister underlying illness. Threshold for admission should therefore be low. Liaison with the transplant centre should take place at an early stage. A high index of suspicion must be maintained for infection, rejection and vasculopathy.

Infection

Infection should be sought and treated aggressively. Broad spectrum antibiotics may be used until culture results become available. Opportunistic infections must be considered, e.g. CMV may be identified on serological testing and can be treated with gancyclovir.

Rejection

This is diagnosed on endomyocardial biopsy. The severity of rejection is graded and treatment determined accordingly. The mildest cases need not be treated. The next grade may be managed with a temporary increase in steroid regime. Severe rejection requires lympholytic therapy with antithymocyte globulin. Plasmapheresis may be used when rejection is antibody mediated.

Ischaemia due to graft vasculopathy

Thrombolysis tends to be unhelpful for transplant patients. With the absence of pain, it is difficult to be confident about the time course of an ischaemic event. Often the patient will have felt unwell for a while before presenting to hospital. Revascularisation, either with balloon angioplasty and stenting or with surgery is often not feasible because the disease is diffuse. Management of transplant patients presenting due to myocardial ischaemia tends to be directed towards medical therapy for complications such as heart failure or arrhythmia. It is necessary to investigate for graft vasculopathy and also to exclude graft rejection. The only definitive treatment for vasculopathy is re-transplantation. Even when this can be accomplished, it tends to have a much poorer outcome the second time around.

A minority of transplant patients may present with ischaemic chest pain. On these occasions they can be managed much more like a conventional acute coronary syndrome with respect to the timing of the onset of pain and attempting thrombolytic therapy or urgent percutaneous intervention. Although graft vasculopathy is a diffuse process, there are many instances of individuals having a target for percutaneous coronary intervention (PCI). An artery with significant thrombus in its lumen has the potential for intervention. Therefore, although angiography may simply demonstrate severe diffuse disease with no potential for revascularisation, an attempt should be made to image the coronary arteries promptly if there is good reason to suspect ischaemia. A patient who has had his transplant a few years previously and who presents with new evidence of heart failure, a suspicious ECG and a troponin rise should be discussed with the cardiologists at an early stage with a view to imaging his coronaries.

Heart failure and arrhythmias

Myocardial ischaemia will most commonly present with heart failure or arrhythmias. Rhythm disturbances may present with palpitations, dizziness or syncope. Heart failure may be treated with diuretics and nitrates. Beta blockers must be used with caution. Hypertension and hypercholesterolaemia are common problems for transplant patients and they should receive aggressive secondary prevention if vascular disease is diagnosed.

• Heart transplant patients may have a life threatening infection without being overtly septic
• Symptoms of graft rejection may be vague and non-specific index of suspicion needs to be high
• Because of denervation, ischaemia of the transplanted heart is seldom associated with pain
• Conventional management strategies for ischaemic events are often ineffective
• Recipient P waves may lead to inappropriate diagnosis of AV block
• Atropine is ineffective for bradyarrhythmias because the heart is denervated
• Beta blockers must be used with caution because transplant patients rely on circulating catecholamines to increase their cardiac output

• Transplant patients are immunosuppressed. When infection occurs, it may not be obvious. One should have a high index of suspicion and a low threshold for antimicrobial therapy
• As well as increasing susceptibility to infection, immunosuppressants may have toxic effects on various organs. They also significantly increase the risk of malignant disease, such as lymphoproliferative disorder
• Graft rejection is often asymptomatic and detected on endomyocardial surveillance biopsy. If the patient becomes compromised, they will have signs and symptoms of heart failure
• Graft vasculopathy is the major factor affecting long term survival for heart transplant patients. The ischaemia caused is often painless
• Graft vasculopathy is concentric and diffuse and therefore tends not to be amenable to conventional reperfusion interventions
• Atrial fibrillation and flutter are common following transplantation. They become more common when rejection occurs
• Sinus node disease is the most common form of bradyarrhythmia following a heart transplant. It usually occurs soon afterwards, and may be due to ischaemia or trauma during surgery
• Later, AV block may occur. This needs to be distinguished from artefact caused by a recipient p wave. When AV block is genuine, rejection and graft vasculopathy should be considered as an underlying cause

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