Amyloidosis is a group of diseases caused by the accumulation of abnormally folded proteins in tissues and organs. Although traditionally considered rare, transthyretin amyloidosis is increasingly recognized as an important and underdiagnosed cause of heart failure, neuropathy, and disability—especially in older adults.
What Is Amyloidosis?
Proteins normally fold into precisely defined three-dimensional structures that determine their biological function. If this folding process fails, certain proteins can aggregate into insoluble, β-sheet-rich fibrils known as amyloid. These deposits accumulate in tissues and progressively impair organ function.
Several types of systemic amyloidosis exist. The most important are:
Correct identification of the amyloid type is essential because treatment differs fundamentally between these disorders.
ATTR Amyloidosis: The Heart and Nervous System Are Particularly Affected
Transthyretin (TTR) is mainly produced in the liver and normally circulates as a stable tetramer. If this tetramer becomes unstable, it can dissociate into monomers that misfold and form amyloid fibrils.
Two major forms are distinguished:
Wild-type ATTR amyloidosis (ATTRwt) is not inherited and occurs predominantly in older adults, especially men. The heart is usually the main affected organ.
Hereditary ATTR amyloidosis (ATTRv) results from pathogenic variants in the TTR gene and can affect both the heart and the peripheral and autonomic nervous systems.
Typical cardiac manifestations include progressive shortness of breath, reduced exercise capacity, edema, atrial fibrillation, conduction abnormalities, dizziness, and heart failure.
Neurological manifestations may include burning pain, tingling or numbness in the feet and hands, impaired temperature sensation, progressive muscle weakness, orthostatic hypotension, gastrointestinal disturbances, bladder dysfunction, and erectile dysfunction.
Important Red Flags
Several apparently unrelated disorders may precede cardiac ATTR amyloidosis by years. Important warning signs include:
ATTR amyloidosis should therefore be considered particularly when cardiac abnormalities occur together with one or more extracardiac red flags.
Diagnosis Has Become Much Easier
Echocardiography is usually the first imaging examination when cardiac amyloidosis is suspected. Increased ventricular wall thickness, diastolic dysfunction, biatrial enlargement, and a characteristic strain pattern with relative apical sparing may raise suspicion.
Cardiac magnetic resonance imaging can further demonstrate an infiltrative cardiomyopathy.
An essential diagnostic step is the exclusion of AL amyloidosis using:
If these tests show no evidence of a monoclonal protein, bone-tracer scintigraphy with 99mTc-DPD, HMDP, or PYP can often establish the diagnosis of ATTR cardiomyopathy without the need for an endomyocardial biopsy. Strong myocardial tracer uptake in the appropriate clinical setting is highly suggestive of ATTR-CM.
Once ATTR amyloidosis has been confirmed, TTR genetic testing should distinguish hereditary ATTRv from wild-type ATTRwt.
Treatment Has Changed Dramatically
For many years, treatment was largely limited to controlling heart failure symptoms. Today, several therapies can directly interfere with the disease process.
Tafamidis and acoramidis stabilize the TTR tetramer and reduce its dissociation into amyloid-forming monomers.
Tafamidis has demonstrated reductions in mortality and cardiovascular hospitalizations in ATTR cardiomyopathy. Acoramidis also significantly improves a combined outcome including mortality, cardiovascular hospitalization, NT-proBNP, and functional capacity.
A second strategy is to reduce the production of transthyretin in the liver.
Vutrisiran, an RNA-interference therapy administered subcutaneously every three months, reduces hepatic TTR synthesis. In the HELIOS-B trial it reduced the risk of all-cause mortality and recurrent cardiovascular events in patients with ATTR cardiomyopathy.
Patisiran also suppresses TTR production and has demonstrated benefits in functional capacity in ATTR cardiac amyloidosis, although its current European indication remains hereditary ATTR amyloidosis with polyneuropathy rather than ATTR cardiomyopathy.
Supportive cardiac treatment remains essential. Loop diuretics are central for controlling congestion and edema. Conventional heart-failure medications such as beta-blockers, ACE inhibitors, ARBs, or ARNI require careful individual assessment because hypotension and reduced cardiac output may limit their tolerability. Mineralocorticoid receptor antagonists and SGLT2 inhibitors appear promising in ATTR-CM, although much of the evidence remains observational.
Patients with atrial fibrillation generally require oral anticoagulation because cardiac amyloidosis is associated with a particularly high risk of intracardiac thrombus formation and embolic complications.
Why Early Diagnosis Matters
The major therapeutic advances in ATTR amyloidosis have transformed a previously largely untreatable disease into one for which several disease-modifying therapies are now available.
However, current treatments primarily slow further amyloid formation and disease progression rather than rapidly removing established amyloid deposits. The greatest opportunity therefore lies in recognizing ATTR amyloidosis before advanced irreversible cardiac or neurological damage has developed.
Bilateral carpal tunnel syndrome, unexplained ventricular wall thickening, heart failure in an older patient, polyneuropathy, and autonomic dysfunction should no longer be viewed as isolated findings when they occur together. They may represent the first clues to transthyretin amyloidosis.