Diagnosis of Cardiac Amyloidosis

The following tests help doctors to make a diagnosis of cardiac amyloidosis:

Electrocardiogram (ECG)

The ECG test is a safe, rapid, painless method whereby the electrical impulses in the heart can be detected, measured and represented as a tracing on graph paper.

All patients with suspected amyloidosis should have an ECG. Most patients referred to the NAC have already had an ECG. We also perform this test if required. The findings can be helpful in making the diagnosis of cardiac amyloidosis. Some ECG appearances are characteristic of amyloidosis in the heart. This is especially true when the echocardiogram also shows particular findings.

ECG patterns can also provide clues to differentiate between AL and TTR amyloidosis. Progressive ECG changes may be useful in assessing silent progression of heart disease. After treatment of AL amyloidosis there is usually no change seen in the ECG, but sometimes ECG changes may improve.

Blood tests for diagnosis of cardiac amyloidosis: cardiac biomarkers

When heart muscle is damaged by amyloid deposits, specialist blood tests may detect raised levels of:

• NT-proBNP:  N-terminal fragment of brain natriuretic peptide

and:

• High sensitivity troponin

These are known as cardiac biomarkers. High levels of these 2 markers in blood tests may be due to severe heart disease.  But since NT-proBNP is partially cleared from the body by the kidneys, raised levels may reflect kidney disease rather than heart disease.  This test is therefore most useful in patients with normal kidney function.

The results of these blood tests often help to provide doctors with information in AL amyloidosis patients. This information may be used to stage and evaluate risk at the time of diagnosis and to assess treatment response.  The levels of NT-proBNP may fall dramatically within weeks after chemotherapy, before any change is observed on echocardiography or cardiac MRI.  Patient outcome is often good when a dramatic fall is observed.  But there is sometimes a transient early increase in NT-proBNP in patients receiving the immunomodulatory drugs, thalidomide and lenalidomide.  The reason for this is unknown.

Echocardiogram for diagnosis of cardiac amyloidosis

Echocardiography is a type of ultrasound test. In this type of test reflections of sound waves are used to build up a detailed picture of organs inside the body. It is safe and painless and does not involve any exposure to radiation.

The ultrasound technician uses gel to improve skin contact on the chest with a piece of equipment called a transducer. The transducer aims sound waves in the direction of the heart and detects the waves that reflect (echo) back. The sound waves cannot be heard as they are high frequency, outside the audible range for our ears.

The ultrasound machine detects the waves echoing back and converts them into a detailed picture of the heart, which the technician views on a screen like a television screen. Doctors who know how to interpret these pictures can obtain a wide variety of detailed information about the structure and functioning of the heart.

All patients with suspected amyloidosis should have an echocardiogram. When amyloidosis in the heart is advanced, it is usually clearly visible on the echocardiogram. However, the findings may be less clear at the early stages of amyloid heart disease.

When amyloidosis affects the heart, the walls of the large heart chambers known as ventricles are evenly thickened. The heart appears stiffened. Although the heart muscle may contract normally, due to the stiffness it does not fully relax. This failure to relax properly is called “diastolic dysfunction”. It is usually the earliest abnormal finding to become apparent on echocardiography. There may be diastolic dysfunction before there are even any symptoms of heart disease. However, it should be born in mind that diastolic dysfunction is also commonly seen in other diseases, and is by no means diagnostic of amyloidosis.

When ATTR amyloid deposits affect the heart there is often also thickening of the heart valves visible on echocardiography.

Cardiac Magnetic Resonance (CMR) scans for diagnosis of cardiac amyloidosis

CMR is a method whereby a magnetic field and radio waves are used to obtain detailed pictures of the heart. It is safe and painless, and does not involve any exposure to radiation.

CMR is not currently available in the NAC, but patients may be referred to another hospital for this type of scan if necessary.

Before the scan, contrast material may be injected into the patient’s vein. During the scan, patients lie still inside a closed “tunnel” type of scanner for up to one hour. The pictures produced by the computer can then be examined by doctors.

In many ways the information provided by CMR is similar to that provided by echocardiography. However, in some patients, echocardiography may not be able to determine whether heart wall thickening is due to amyloidosis or to another cause such as hypertension. In such patients, CMR imaging can help to distinguish between these different causes of heart wall thickening.

When doctors analyse the CMR scans, they can often clearly visualise the amyloid deposits within the heart walls, between the heart cells. It is expected that in the future it may be possible to use CMR to accurately measure the size of the amyloid deposits within the heart wall. Such measurements could then be repeated to follow the build-up of amyloid deposits and their regression with treatment.

Heart biopsy for diagnosis of cardiac amyloidosis

Heart muscle biopsy is considered the “gold standard” for diagnosing amyloid deposits in the heart. This means that it is the best available test, against which all other tests are measured.

If it is necessary, we refer patients to a cardiologist for this test, which usually takes less than an hour.

The test involves removal of a small sample of heart muscle. Patients are usually sedated. Then the doctor numbs a small area of skin in the neck, and cuts through the skin, into a blood vessel that leads directly to the heart. A long, narrow tube called a catheter is inserted into the blood vessel. The catheter is threaded through the blood vessel to the heart. X-rays are performed to ensure that the catheter tip is positioned next to the heart wall. Then a grasping device at the end of the catheter is used to remove a tiny sample of heart tissue. The catheter is then withdrawn, bringing the heart tissue with it. The tissue is sent to the laboratory for analysis.

The procedure is usually safe and painless, and does not require admission to hospital. There may be minor discomfort when the skin is cut and the catheter inserted. This is usually prevented by sedation and application of local anaesthetic to the skin which numbs the area. There may be some bleeding from the cut in the neck. This is usually easy to control with local pressure. There is a very small risk that the procedure may damage the heart wall or cause an abnormal heart rhythm. Patients are monitored after the procedure to ensure that all is well before they go home.

Endomyocardial biopsy is most commonly required when:

• There is a need to distinguish between AL and ATTR amyloidosis.
• Amyloid fibril type cannot be identified by other means.
• A patient has amyloid only affecting the heart.
• A patient has heart wall thickening on the echocardiogram and causes other than amyloid have been ruled out.

Radionuclide imaging (DPD scans) for diagnosis of cardiac amyloidosis

SAP scanning does not provide adequate information about body organs that are moving.

The heart is in constant motion, contracting and relaxing as it pumps blood around the body. Therefore, SAP scanning is not of use for assessment of amyloid deposits in the heart.

However, a different radioactive marker that does detect amyloid in the heart has recently been identified. This marker is called 99mTc-DPD, or just DPD.

How DPD scans work

DPD is a type of “bone-seeking” tracer. When it is injected into the bloodstream it is mainly taken up by bones all through the body. It is taken up most strongly in bone regions in which there is disease or abnormality. In some countries in Europe DPD is used routinely in bone scans to detect a variety of bone illnesses. In the UK it was used for bone scans in the past, but at present other tracers are preferred.

Over the last 30 years there have been several case reports in which bone-seeking tracers appeared to home in on amyloid deposits in the heart, as well as detecting bone abnormalities. However, these were generally viewed as incidental findings occurring in patients who underwent bone scans for other reasons than amyloidosis.

In recent years this approach has been investigated systematically for the first time.   Since 2010 we have performed hundreds of DPD scans on patients at the NAC with suspected amyloid in the heart. They are also performed in some other European amyloidosis centres.  The results have been impressive, and have contributed significantly to our ability to evaluate patients with cardiac amyloidosis.

Benefits of DPD scans

It turns out that:

• DPD is very sensitive at detecting amyloid deposits in the heart.
• DPD scans are most useful when the amyloid deposits are of TTR type.
• The amount of DPD taken up by the heart correlates very closely to the size of ATTR amyloid deposits.
• Asymptomatic ATTR amyloid deposits can be detected in the heart by DPD scans at an early stage, when other heart tests appear normal.
• DPD scans are less useful for detecting and evaluating AL amyloid deposits in the heart.
• DPD uptake in the heart only occurs in about 1 in 3 patients with AL amyloid in the heart.
• Even when there is DPD uptake by AL amyloid deposits in the heart, the amount of uptake does not correlate well with the size of deposits.

At the NAC, we combine the DPD scan with a type of CT scan called a Single Positron Emission Computerised Tomography (SPECT) scan.

The procedure is as follows:

1. The DPD tracer is injected into the patient’s vein.
2. Scans are performed 5 minutes after injection, then 3 hours after injection.
3. For each scan, the patient lies down on the scanner and there is a scan consisting of a “whole body sweep”, which shows the entire body.
4. The scanning camera is rotated and a type of CT scan called a SPECT of the heart is performed while the patient remains in the same position. At the same time a routine high resolution X-ray CT scan is obtained.

When the DPD scan and the SPECT scan are overlaid by the computer they provide the doctors with detailed and 3 dimensional information, showing both the anatomy (structure) of the heart and the pathology (amyloid deposits) in the heart.

The initial DPD whole body sweep may be helpful in the following ways:

• If there is no amyloid in the heart, the whole body sweep just shows the bones, as all the tracer goes into the bones, and none is taken up in the heart.
• In 2 out of 3 patients with AL amyloid deposits in the heart, the whole body sweep just shows the bones, as all the tracer goes into the bones, and none is taken up in the heart.
• In 1 out of 3 patients with AL amyloid deposits in the heart, the whole body sweep shows tracer uptake in both the heart and the bones.
• In patients with ATTR amyloid deposits in the heart, the whole body sweep shows tracer uptake in both the heart and the bones.
• By comparing the intensity of tracer uptake in the heart with uptake in the bones, doctors can assess the size of ATTR amyloid deposits in the heart.
• For AL amyloid deposits, intensity of tracer uptake in the heart does not correlate with size of amyloid deposits.

DPD scanning and SPECT are safe tests. There may be minor discomfort when the tracer is injected, but the tests are otherwise painless. There is some exposure to radiation from the tracer and from the CT scan.

Use of DPD scanning for early diagnosis

DPD scans can detect ATTR amyloid deposits in the heart before other tests. It may be helpful in guiding treatment decisions, including timing of liver transplantation in:

• Asymptomatic patients who are known to carry mutations in the TTR gene that cause familial amyloid polyneuropathy.
• Patients with early familial amyloid polyneuropathy who do not yet have heart failure symptoms.