How to spot ATTR-CM

Early and accurate diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) is crucial to ensure that patients receive the appropriate care, highlighted leading experts in a state-of-the-art review of the disease.

“Prognosis [of ATTR-CM] worsens rapidly with continued amyloid deposition and subsequent advancing organ dysfunction. Unfortunately, diagnosis is often delayed owing to low disease awareness or misdiagnosis,” stated the expert panel led by Dr Ronald Witteles, Stanford University School of Medicine in Stanford, California, US. [J Am Coll Cardiol HF 2019;7:709-716]

“Early, accurate diagnosis is therefore key to improving patient outcomes, particularly in the context of both the recent approval of tafamidis in some countries for ATTR-CM, and of other promising therapies under development … which offer future treatment options for a disease which previously had none,” they added.

Underdiagnosed and misdiagnosed

ATTR-CM is an infiltrative disease of the heart muscle that is caused by deposition of transthyretin amyloid fibrils in the heart, which can lead to heart failure (HF) and arrhythmias.

Due to perceived rarity of the disease, ATTR-CM is often underdiagnosed, the experts noted. Coupled with heterogeneity of symptoms at presentation and overlap of symptoms with other conditions, diagnosis of ATTR-CM can be a challenge. It is frequently misdiagnosed as hypertensive heart disease and when treated as such, can lead to clinical worsening.

“It is therefore crucial that physicians are aware, not only of ATTR-CM, but also of appropriate assessments, diagnostic tools, and clues within the patient’s medical and family history that can help to elucidate aetiology,” stressed Witteles and co-authors.

Red flags

The presence of “increased wall thickness with either HF or red flag signs/symptoms [described below] in men older than 65 years or women older than 70 years” should warrant a diagnostic test for ATTR-CM, the experts said.

On echocardiography, a decreased longitudinal strain with apical sparing can help differentiate cardiac amyloidosis from other causes of left ventricular (LV) thickening.

On the electrocardiogram (EKG), QRS voltages that do not match the LV thickness may hold a clue to ATTR-CM. Also, atrioventricular block in the presence of LV thickening is another indicative feature.

In addition, evidence of infiltrative features, such as increased thickness of the atrioventricular valves, right ventricular free wall, and interatrial septum, should alert clinicians to ATTR-CM. Furthermore, pronounced extracellular volume expansion, abnormal nulling time for the myocardium or diffuse late gadolinium enhancement on CMR* should raise suspicion of ATTR-CM.

In terms of biomarkers, persistent increase in serum troponin levels is another red flag of ATTR-CM, according to the experts.

Apart from findings based on the heart, systemic involvement manifesting in the autonomic and/or peripheral nervous system — co-existing along with cardiac dysfunction — may raise an ATTR-CM alarm.

ATTR-CM has two subtypes: wild type (ATTRwt) and hereditary/mutant (ATTRm) ATTR — each with associated extracardiac manifestations. While neurologic manifestations for ATTRm can take the forms of bilateral ascending sensory-motor polyneuropathy and/or dysautonomia, bilateral carpal tunnel syndrome, lumbar spinal stenosis, and bicep tendon rupture are common in ATTRwt.

“Bilateral carpal tunnel syndrome is often one of the earliest indicators of ATTR-CM, is the most common noncardiac manifestation, and can precede clinical HF by several years,” the experts highlighted.

“Given that it is not possible to reliably distinguish between ATTRm and ATTRwt by clinical or histologic techniques, TTR gene sequencing is recommended for the definitive diagnosis in all forms of confirmed ATTR-CM,” suggested Witteles and co-authors.

“Tafamidis, a TTR stabilizer, has been approved in some countries for the treatment of hereditary and wild-type forms of ATTR-CM,” they pointed out.

Definitive diagnosis

Once ATTR-CM is suspected, definitive diagnosis can be achieved noninvasively through bone scintigraphy using technetium-labelled bisphosphonates with high sensitivity and specificity.

To rule out light-chain (AL) amyloidosis, the experts recommend conducting serum and urine test for monoclonal protein.

“Histologic confirmation [through endomyocardial biopsy] is still needed in cases where both bone scintigraphy and tests for monoclonal protein are abnormal,” the experts pointed out.