TTR protein clumps may help drive blood vessel damage in ATTR-CM

In people with transthyretin amyloid cardiomyopathy (ATTR-CM), the buildup of faulty transthyretin (TTR) protein in the heart may contribute to blood clots that block capillaries, the smallest blood vessels, and trigger molecular events that ultimately lead to heart damage, according to a new study.

The researchers’ proposed mechanism, based on detailed analyses of diseased heart tissue collected from two people with late-stage ATTR-CM who underwent a heart transplant, suggests that the disease may also be a microangiopathy — a condition affecting the body’s smallest blood vessels.

The findings may have implications for ATTR-CM treatments such as Vyndamax (tafamidis), which is designed to stabilize TTR and help prevent new toxic TTR clumps, known as amyloid deposits, from forming. The researchers suggested that such treatments may be more helpful earlier in the disease process, before substantial clots and downstream damage have occurred.

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The data were described in the study “Three‐Dimensional Visualization and Proteomic Analysis of Human Cardiac Transthyretin Amyloidosis Tissue Reveals Microangiopathy and Capillary Occlusion,” published in the Journal of the American Heart Association. The work was funded in part by the National Institutes of Health.

ATTR-CM is marked by a faulty, or misfolded, TTR protein that is prone to form toxic clumps that accumulate mainly in the heart. The disease may be caused by mutations in the gene that encodes TTR, or it can develop with age in the absence of mutations.

Although evidence supports TTR clumping as a driver of heart damage in ATTR-CM, the exact biochemical mechanisms by which these aggregates lead to heart damage are not fully understood.

Previous studies aimed at understanding these mechanisms have often relied on tissue analyses using very thin slices of heart tissue, which allows tissue visualization under a microscope. However, the human heart exists in three dimensions (3D), and looking only at thin slices means researchers haven’t been able to get a full 3D view of how ATTR-CM affects heart tissue.

Here, a team of researchers in the U.S. collected the diseased hearts from two Black adults with late-stage ATTR-CM — a 63-year-old man with a disease-causing TTR mutation and a 57-year-old woman without a TTR mutation — during heart transplantation. They also obtained a heart from a deceased 60-year-old man of Caribbean/Puerto Rican descent with no known cardiovascular history.

3D imaging reveals capillary clots near TTR deposits

To visualize heart tissue in 3D using samples much thicker than have been used in prior studies, the researchers used methods to remove lipids, or fatty molecules, that can make it hard to see through tissue.

Heart muscle contains a lot of capillaries, or tiny blood vessels, which provide a constant supply of oxygen and nutrients needed for the busy work of constantly pumping. The researchers found that areas with lots of TTR clumps generally also had blood clots that blocked these vessels.

In fact, in the ATTR-CM hearts, areas thick with protein clumps generally had abnormally few blood vessels, while nearby areas showed increased but disorganized blood vessel growth.

The researchers paired their 3D tissue data with proteomics analysis, which identified 792 unique proteins in the heart samples. They found that, in addition to higher TTR, ATTR-CM hearts had higher levels of clotting proteins, as well as proteins involved in immune inflammation and the growth of new blood vessels.

Taking these findings collectively, the researchers proposed a biochemical model for how faulty TTR may drive heart damage in ATTR-CM. Basically, the model proposes that activation of cells lining the heart’s capillaries — possibly triggered by misfolded TTR — may set off clotting and inflammation that block these tiny blood vessels.

This lowers the amount of oxygen that reaches that section, triggering inflammation and damage to the cells that line those tiny vessels. That damage may allow misfolded TTR to anchor to nearby structural molecules and form toxic clumps.

The body’s natural repair systems then may try to restore blood flow by growing new blood vessels. However, TTR amyloid deposits may interfere with organized blood vessel growth.

This model is consistent with imaging studies done in people with ATTR-CM, which have found poor blood flow to heart muscle.

Findings may apply to different forms of ATTR-CM

The team also emphasized that the observed patterns of damage were essentially identical in both patients, suggesting this mechanism may apply broadly in ATTR-CM regardless of whether the disease is genetic or age-related.

The scientists cautioned, however, that because the study was based on samples from two late-stage ATTR-CM patients, it is impossible to draw definitive conclusions about the exact order of events in their proposed mechanism. Still, they said their data “has generated several hypotheses meriting further scrutiny.”

The team also noted that, if the proposed mechanism is true, it could have important implications for ATTR-CM treatments. For example, the daily oral therapy Vyndamax, sold by Pfizer, is designed to stabilize TTR and help prevent new amyloid deposits from forming. Based on their model, the researchers suggested this type of treatment may be more helpful earlier in the disease process, before substantial clots and downstream damage have occurred.