Advances in ATTR-CM call for early diagnosis

Diagnostic advances and new therapies for transthyretin cardiomyopathy (ATTR-CM) have transformed the treatment landscape of ATTR-CM, according to a review.

“ATTR-CM can now be diagnosed noninvasively without a biopsy,” said the review authors Drs Jonah Rubin and Mathew Maurer from the New York-Presbyterian/Columbia University Medical Center in New York, US. [Annu Rev Med 2020;71:203-219]

Bone nuclear scintigraphy has recently emerged as a noninvasive diagnostic tool for ATTR-CM in the absence of monoclonal proteins, with 92-percent sensitivity and 95-percent specificity. [Eur J Nucl Med Mol Imag 2018;45:1945- 1955] “[N]uclear scintigraphy has enabled broader evaluation and detected [wild-type] ATTR-CM more frequently than expected,” the experts said.

However, nuclear scintigraphy may only be applicable to ATTR-CM and not to immunoglobulin light chain CM (AL-CM), the other CM subtype. “AL-CM still requires a biopsy,” they stressed.

While endomyocardial biopsy remains the gold standard for diagnosing ATTR-CM, its invasive nature limits its use to scenarios when significant markers are present. The technical expertise required to perform the procedure and interpret the results accurately are also potential limiting factors.

AL-CM may render a false positive result on bone scintigraphy and confound the distinction between ATTR-CM and AL-CM, the researchers pointed out. As such, laboratory testing on top of scintigraphy is required to rule out ALCM. “Once ATTR-CM is diagnosed, genetic testing is employed to subtype it as either wild-type or hereditary,” they said.

Extracardiac signs

Given the diverse presentation patterns of CM and its subtypes, a keen sense of noncardiac red flags is crucial for a prompt and accurate diagnosis of ATTR-CM, noted the researchers.

“[Wildtype ATTR-CM] is often preceded, several years before onset, by orthopaedic clues, including carpal tunnel syndrome, lumbar spinal stenosis, hip and knee arthroplasty, and biceps tendon rupture,” they said.

Sensorimotor polyneuropathy may be present in variant ATTR-CM (also known as hereditary ATTR-CM), which is specifically driven by a predominantly neuropathic mutation, noted the researchers. Other mutations may cause a mixed phenotype with both cardiac and neurologic involvement. [Heart J 2013;34:520-528]

The silencers, stabilizers

“[T]he advent of several promising treatments have ushered in a new and exciting era that renders early diagnosis of paramount importance,” said Rubin and Maurer.

ATTR silencers (eg, patisiran, inotersen) prevent synthesis of transthyretin, while ATTR stabilizers (eg, diflunisal, tafamidis) prevent dissociation of transthyretin tetramers into monomers. Tafamidis is the first FDA-approved ATTR stabilizer specifically for ATTR-CM.

Initially approved in Europe for familial amyloid polyneuropathy, tafamidis has subsequently been found to reduce the incidence of all-cause death and cardiovascular-related hospitalizations, and improve functional capacity and quality of life in patients with ATTR-CM. [N Engl J Med 2018;379:1007-1016]

The researchers pointed out that the silencers, on the other hand, were FDA-approved for polyneuropathy in variant ATTR-CM and those with concomitant neuropathy, but not for isolated ATTR-CM cases.

While these treatments prevent further disease progression, the researchers noted that their ability to reverse the phenotype is not well established. “As more therapies gain FDA approval, future research must investigate whether one therapy is superior to another, and if combination therapy has any role,” they added.