Heart scans detect early changes in hATTR-PN carriers

People carrying mutations known to cause hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) who are not yet showing symptoms may already have disease-associated toxic protein clumps in the heart, a study suggests.

Greater heart abnormalities were also associated with more signs of nerve damage — the hallmark of hATTR-PN — suggesting that heart scans may help detect disease involvement before conventional tests identify clear neurological symptoms.

The findings indicate that abnormalities in heart imaging scans “can be surrogate biomarkers for improving early and accurate diagnosis and decision-making for early intervention,” in people carrying hATTR-PN-causing mutations, the researchers wrote.

The study, “Subclinical cardiomyopathy in premanifest carriers of late-onset hereditary transthyretin amyloidosis with polyneuropathy,” was published in the Journal of the Formosan Medical Association.

hATTR-PN is typically caused by inherited variants in the TTR gene leading to the production of abnormal transthyretin protein (TTR) that is prone to form toxic clumps, called amyloid deposits. In people with hATTR-PN, these aggregates mainly accumulate in peripheral nerves (those outside the brain and spinal cord), resulting in damage to multiple nerves (polyneuropathy). Amyloid deposits may also build up in other organs, including the heart muscle, causing damage known as cardiomyopathy.

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Early detection enables early treatment

People with disease-causing TTR mutations may have signs of amyloid deposits and associated tissue damage before noticeable symptoms appear. Detecting these early changes is important as hATTR-PN treatments are most effective at slowing disease progression when started early in the disease course.

A team of researchers in Taiwan investigated heart involvement and its relationship with nerve damage in people carrying TTR variants known to cause hATTR-PN but not yet showing clear symptoms (premanifest carriers).

They analyzed data from 32 premanifest carriers, 11 people with early-stage hATTR-PN, and 63 healthy controls. Most participants were men. The median age was 47 for healthy controls, 51 for premanifest carriers, and 64 for manifest hATTR-PN patients.

p.A117S was the most common TTR mutation, detected in 96.9% of premanifest carriers and 81.1% of manifest patients. This variant is common in Taiwan and other parts of Asia and is associated with late-onset disease (symptom onset at age 50 or older).

Nerve conduction tests, which assess signal transmission speed along peripheral nerves, found no evidence of polyneuropathy among premanifest carriers. However, 38% of them had carpal tunnel syndrome, a condition that affects a nerve in the wrist and can be an early warning sign of hATTR-PN.

Analyses of skin samples under the microscope showed fewer-than-normal small nerve fibers in 22% of premanifest carriers. Some had subtle abnormalities in sensory function or the autonomic nervous system, which regulates involuntary body functions such as heart rate and blood pressure.

By comparison, all participants with manifest hATTR-PN had evidence of polyneuropathy on nerve conduction tests, 91% had carpal tunnel syndrome, and 70% had reduced numbers of small nerve fibers. These findings suggest that some nerve abnormalities may be present in people carrying disease-associated TTR mutations before conventional tests detect nerve damage.

Heart MRI scans showed that, even after adjusting for age and sex, premanifest carriers had significantly greater extracellular volume (ECV) and longer native T1 — two key indicators of heart amyloidosis burden — than healthy controls.

Premanifest carriers also had significant changes in heart structure, such as a higher left ventricular mass index (LVMi), indicating a larger left lower heart chamber, which is a common sign of amyloid deposits.

Using reference ranges established from healthy controls, researchers found abnormally high ECV in 25% of premanifest carriers, prolonged native T1 in 11%, and an increased LVMi in 6%. One carrier who underwent a heart muscle biopsy was confirmed to have TTR amyloid deposits.

“These results suggest evidence of early [heart] amyloidosis among carriers with TTR variants,” the researchers wrote.

People with established hATTR-PN had significantly more pronounced abnormalities in heart imaging measures than premanifest carriers. A specialized heart imaging scan also found signs suggestive of amyloid deposits in five carriers (16%) and all hATTR-PN patients.

The Mayo risk score for TTR-related cardiomyopathy was also higher among patients with established disease: 55% had scores indicating high risk, compared with none of the premanifest carriers. Among carriers, higher scores were significantly associated with more pronounced imaging markers of heart amyloid deposits and structural changes.

Among premanifest carriers, more pronounced abnormalities on cardiac imaging were significantly associated with greater signs of nerve damage, including in small nerve fibers involved in temperature sensation and autonomic function, as well as in larger nerve fibers responsible for movement and sensation.

“This study provides [heart] imaging evidence of [heart] amyloidosis among premanifest carriers with the TTR variants of late-onset [hATTR-PN],” the researchers wrote.

Further studies that follow patients over time and monitor both polyneuropathy and cardiomyopathy are needed to determine whether these imaging markers can predict disease progression and identify people who may benefit from earlier intervention, the team said.