ATTRwt

ATTRwt stands for wild-type transthyretin amyloidosis, a form of transthyretin amyloidosis caused by deposition of misfolded wild-type transthyretin amyloid fibrils. It is distinct from hereditary (ATTRv) forms caused by mutations in the TTR gene. ATTRwt has historically been called senile systemic amyloidosis when it involves multiple organs, and when the heart is predominantly affected it presents as a restrictive cardiomyopathy.

Pathophysiology and presentation: transthyretin is produced mainly by the liver. With aging, the transthyretin tetramer can destabilize and dissociate, allowing misfolded monomers to aggregate into amyloid fibrils that deposit in the myocardium and other tissues. Cardiac involvement leads to stiff, noncompliant ventricles and diastolic dysfunction, often resulting in heart failure symptoms with preserved ejection fraction. Extra-cardiac manifestations may include carpal tunnel syndrome, biceps tendon rupture, and spinal stenosis, which can precede cardiac symptoms.

Diagnosis: suspicion arises in older adults with heart failure symptoms and a restrictive cardiomyopathy pattern. Noninvasive testing includes echocardiography and cardiac MRI, which may show concentric left ventricular thickening and characteristic tissue features. Nuclear scintigraphy with technetium-labeled tracers (such as PYP) often shows significant uptake; when there is no evidence of a plasma cell disorder, this supports ATTR cardiomyopathy. Confirmation typically requires tissue biopsy with Congo red staining and TTR immunostaining, and genetic testing is used to distinguish ATTRwt from ATTRv.

Treatment and prognosis: management focuses on relieving heart failure symptoms and addressing arrhythmias or conduction disease. Disease-modifying therapies that stabilize transthyretin, such as tafamidis, have shown benefit in reducing mortality and cardiovascular events in ATTR cardiomyopathy. Liver transplantation is not used for ATTRwt. Prognosis varies with disease stage; earlier diagnosis and access to stabilizing therapies generally improve outcomes.