Scientists ID blood markers that predict heart risk in ATTR-CM
Study ties higher levels of fibrosis-promoting molecules to worse outcomes
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Blood levels of signaling molecules that promote tissue scarring, or fibrosis, are elevated in people with transthyretin amyloid cardiomyopathy (ATTR-CM), and higher levels of these molecules are associated with worse clinical outcomes for ATTR-CM patients, a study found.
“Our study highlights the importance of fibrosis-related biomarkers in the [disease biology] and prognosis of [ATTR-CM],” the researchers wrote. “Future studies should focus on validating these findings in larger, multicenter [studies] and explore the utility of these biomarkers in monitoring disease progression and therapeutic response—particularly in the context of specific anti-amyloid and antifibrotic therapies.”
The study, “Profibrotic Biomarkers Correlate with Clinical Presentation and Outcome in Cardiac Transthyretin Amyloidosis,” was published in the International Journal of Molecular Sciences.
ATTR-CM is a disorder in which a protein called transthyretin misfolds and forms toxic clumps in the heart, causing damage and impairing its function. However, the molecular details of heart damage in patients aren’t fully understood.
“Accumulating evidence indicates that [fibrosis contributes] significantly to [heart] dysfunction and possibly to prognosis” in people with ATTR-CM, wrote the researchers, in Germany. Based on that evidence, the team hypothesized that blood levels of fibrosis-related signaling molecules are elevated in ATTR-CM patients and are linked to worse outcomes.
Linking molecules to outcomes
Their study included more than 80 adults showing signs of ATTR-CM. Forty-seven had the hereditary form, caused by mutations in the TTR gene, and 43 had the wild-type form, which develops sporadically with age and is most often seen in older adults.
Another 14 adults carried an ATTR-CM-causing mutation but were not yet showing signs of heart damage (asymptomatic carriers). A total of 21 healthy adults with no signs of heart damage on standard tests were also included. These two groups served as controls.
The team analyzed levels of 14 fibrosis-related biomarkers in blood samples from all participants.
Data showed that people with manifest ATTR-CM had significantly higher levels of 11 of the 14 markers — RAGE/AGE, FGF-23, IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-6, MMP-2, MMP-7, TIMP-2, and TIMP-4 — when compared with asymptomatic carriers and healthy controls.
There were no significant differences in profibrotic molecule levels between the control and asymptomatic carrier groups.
Most markers showed a “natural hierarchy … corresponding to the expected level of symptoms,” the researchers wrote. Levels in controls and asymptomatic carriers were lower than those of people with manifest hereditary ATTR-CM, who in turn had lower levels than those of people with manifest wild-type ATTR-CM.
FGF-23 appeared to be a reliable marker of wild-type ATTR-CM. FGF-23 levels were significantly elevated in people with this disease form when compared with the other three groups, but there were no significant differences between the two control groups and the hereditary ATTR-CM group.
Over follow-up periods as long as 29 months (nearly 2.5 years), 18 patients died or were listed for urgent heart transplant, and 12 were hospitalized due to heart decompensation (when the heart isn’t pumping blood efficiently) and required appropriate treatment.
Statistical analyses showed that higher blood levels of most of the 14 profibrotic molecules were significantly associated with a higher risk of poor outcomes such as death/heart transplant, and heart decompensation.
“Several markers (e.g., MMP-7, RAGE-AGE, IGFBP-1, FGF-23, TIMP-2) were significantly associated with both [poor outcomes],” the team wrote.
The researchers also found that participants in their study could be broadly divided into two groups based on profibrotic markers. The first group consisted of all healthy controls, most asymptomatic carriers, and about half of the hereditary ATTR-CM patients. The other group comprised the remaining people with hereditary ATTR-CM and those with the wild-type form.
People in this second group had worse clinical outcomes, with a higher risk of events such as death or transplant and heart decompensation.
Further analyses identified IGFBP-1, IGFBP-3, IGFBP-4, IGFBP-6, FGF-23, TIMP-2, MMP2, and AGE/RAGE as key markers distinguishing the two groups. A model assessing blood levels of these eight markers showed significant differences between the two control groups and the hereditary and wild-type groups.
“Our findings suggest that profibrotic signaling pathways are not only altered in [ATTR-CM] patients but also play a crucial role in disease progression in addition to established risk prediction parameters,” the researchers concluded. They called for further investigation into how these fibrosis-associated molecules may help guide clinical care.
