Cardiac amyloidosis:
which signs should raise suspicion

Article written and reviewed by Dr Luca Moretti

Cardiac amyloidosis can cause shortness of breath, fatigue, swelling of the legs, reduced exercise tolerance and arrhythmias, but these symptoms are common to many other heart diseases. Suspicion becomes stronger when the cardiac picture is associated with signs that may seem unrelated to the heart, such as bilateral carpal tunnel syndrome, neuropathy, lumbar spinal stenosis, atraumatic biceps tendon rupture, proteinuria or orthostatic hypotension.
None of these findings, on its own, proves the presence of amyloidosis. It is the combination of age, symptoms, thickening of the cardiac walls, ECG findings, blood tests and extracardiac manifestations that indicates when a specific diagnostic work-up is appropriate.

The main red flags include:

• thickened cardiac walls without a sufficient explanation;
• heart failure with preserved or only moderately reduced ejection fraction;
• bilateral carpal tunnel syndrome, especially if it developed years before cardiac symptoms;
• lumbar spinal stenosis or spontaneous biceps tendon rupture;
• peripheral neuropathy or autonomic dysfunction with orthostatic hypotension;
• proteinuria, kidney failure, macroglossia or periorbital purpura in a clinical picture compatible with AL;
• conduction disorders, atrial fibrillation or persistently elevated cardiac biomarkers;
• a family history compatible with hereditary transthyretin amyloidosis.

Cardiac amyloidosis is caused by the deposition of protein fibrils in the myocardium. The two forms responsible for the great majority of clinically relevant cases are transthyretin amyloidosis, or ATTR, and immunoglobulin light-chain amyloidosis, or AL. Distinguishing between them is essential because their origin, prognosis and treatment are completely different.

Cardiac signs: when a thickened heart is not simply hypertrophy

One of the most characteristic findings is increased wall thickness in a non-dilated left ventricle. In amyloidosis, this thickening does not depend only on larger muscle cells, but mainly on amyloid material deposited in the extracellular space.
Suspicion is particularly relevant in an older person with heart failure, aortic stenosis or a clinical picture apparently similar to hypertrophic cardiomyopathy, especially when hypertension and other common causes do not adequately explain the observed wall thickness.

Echocardiography may show diastolic dysfunction, increased thickness of the right ventricle and valves, atrial enlargement, pericardial effusion and a characteristic reduction in longitudinal strain with relative apical sparing. None of these signs is perfectly specific.
The ECG may also provide clues: low voltages relative to wall thickness, a pseudo-infarction pattern or conduction disorders increase suspicion, but low voltages are not present in all patients and their absence does not exclude the disease.

Carpal tunnel syndrome, lumbar spinal stenosis and the biceps tendon: typical signs of ATTR

In ATTR cardiac amyloidosis, some musculoskeletal disorders may appear several years before heart failure. The best known is bilateral carpal tunnel syndrome. Lumbar spinal stenosis, atraumatic rupture of the distal biceps tendon and some tendon or joint disorders have also been described.
These problems are also very common in the general population, so they should not cause alarm when present on their own. Their value increases when they occur in combination, especially in an older man with thickened cardiac walls, heart failure, atrial fibrillation or conduction disorders.

Hereditary ATTR may also cause peripheral neuropathy, pain or loss of sensation in the limbs, gastrointestinal symptoms and autonomic dysfunction with orthostatic hypotension. A family history of neuropathy, cardiomyopathy, pacemaker implantation, heart failure or a diagnosis of amyloidosis may therefore be decisive information.
In wild-type ATTR, by contrast, there is no causative hereditary TTR variant and the condition tends to present at an older age.

AL amyloidosis: why some signs require particular urgency

AL cardiac amyloidosis results from immunoglobulin light chains produced by a plasma-cell clone. It can rapidly involve the heart, kidneys, nerves and other organs, and the diagnostic work-up must be prompt because early hematologic treatment is crucial.
Proteinuria, kidney failure, peripheral neuropathy, macroglossia and purpura around the eyes are findings that may point toward AL in the appropriate clinical context.

It is important not to rely on bone scintigraphy alone before excluding a monoclonal component. The presence of a monoclonal gammopathy can complicate interpretation and, in some cases, make a biopsy with precise amyloid typing necessary.
For this reason, when cardiac amyloidosis is suspected, serum free light-chain testing and serum and urine immunofixation are part of the initial diagnostic pathway.

From suspected amyloidosis to diagnosis

Diagnosis begins with recognition of the phenotype and red flags. Echocardiography and cardiac magnetic resonance imaging may show a compatible pattern, but they do not always identify with certainty the protein that forms the amyloid.
The next step includes testing for a monoclonal component and, when appropriate, bone-tracer scintigraphy. In the absence of evidence of monoclonal proteins, intense cardiac uptake on scintigraphy in a compatible clinical setting may allow a non-invasive diagnosis of ATTR without cardiac biopsy.

If monoclonal proteins are present, if scintigraphy is negative or ambiguous, or if the overall picture is inconsistent, a cardiac biopsy or biopsy of another involved tissue may be necessary. Demonstrating that amyloid is present is not sufficient: it must be correctly typed, because confusing ATTR with AL would lead to completely different treatments.
After a diagnosis of ATTR, the TTR gene is also assessed to distinguish the hereditary form from the wild-type form and to define the implications for family members.

When it is worth discussing it with a doctor

It is not reasonable to screen everyone with carpal tunnel syndrome or mild shortness of breath for amyloidosis. Suspicion becomes concrete when several clues converge: thickened cardiac walls, heart failure without a satisfactory explanation, atrial fibrillation or conduction disorders associated with extracardiac red flags.
A person with previous hypertension who progressively becomes normotensive or hypotensive, or who has troponin or NT-proBNP levels that remain elevated beyond what would be expected from the clinical picture, may also warrant further investigation.

Early diagnosis is more important today than in the past because treatments are available that can modify the natural history of some forms of amyloidosis. This does not mean that every red flag requires immediate specialist testing, but suspicious combinations should not be ignored or automatically attributed to age.
Sudden severe shortness of breath, significant chest pain, syncope or rapid worsening of heart failure still require urgent assessment regardless of the cause.

Frequently asked questions about signs of cardiac amyloidosis

What are the most common symptoms?
Shortness of breath, fatigue, reduced exercise tolerance, edema, palpitations and sometimes dizziness or syncope. These symptoms are nonspecific and should be interpreted together with the other clues.

Does carpal tunnel syndrome mean amyloidosis?
No. It is a very common condition, but if it is bilateral and associated with other red flags, it may increase suspicion of ATTR.

Which signs point particularly toward ATTR?
Bilateral carpal tunnel syndrome, lumbar spinal stenosis, spontaneous biceps tendon rupture, neuropathy and a compatible family history are among the most useful clues.

Which signs point toward AL?
Proteinuria, kidney failure, neuropathy, macroglossia and periorbital purpura may accompany cardiac involvement.

How is the diagnosis confirmed?
With a diagnostic pathway that combines testing for monoclonal proteins, cardiac imaging, scintigraphy and, when necessary, biopsy with amyloid typing.