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Boston University Team Develops Test for Diagnosing Transthyretin Amyloid Cardiomyopathy


NEW YORK (360Dx) – Scientists from the Boston University School of Medicine have developed a test that could help identify patients with transthyretin amyloid cardiomyopathy (ATTR), a significant, but difficult to diagnose, cause of heart failure.

The test, which measures levels of the retinol-binding protein 4 (RBP4) in patient sera, could prove particularly useful in community settings where clinicians may lack the equipment or expertise currently required to diagnose the condition, said Frederick Ruberg, associate professor of medicine and radiology at BUSM and one of the developers of the test.

Ruberg said that he and his colleagues are now preparing a larger validation study for the test as they move toward making it a broadly available tool. He said that while RBP4 can be measured by standard immunoassays like ELISAs, a clinically validated assay for the protein doesn't currently exist, mainly because the protein had not previously been identified as clinically useful.

"We're hopeful that through this study and future validation studies, we'll be able to get RBP4 into a clinical setting," Ruberg said. "So, you could be in a doctor's office and check off a box, and Quest Diagnostics, or whoever does your blood assay, will be able to run the test for you, and you'll get that result back. Just like you would with other immunoassays."

He noted that it is not yet clear whether RBP4 can be sold as a proprietary marker for diagnosing ATTR as the protein was known from previous studies.

"I haven't fully vetted the IP aspects of this technology yet. I'm exploring that possibility with our technology office," Ruberg said, adding that his primary goal is to make the test widely available, regardless of its commercial prospects.

ATTR is challenging to diagnose for several reasons, Ruberg noted. The condition is a less common cause of heart failure than things like high blood pressure or coronary artery disease, but "often lives in the background of these more common things," he said.

"The challenge for the clinician is to figure out which of the patients they are seeing that have coronary artery disease and hypertension also have amyloidosis," he said.

Currently, heart biopsy is the definitive method for diagnosing ATTR, but, Ruberg noted, this approach is not appropriate as a general screening tool.

"It's invasive, it has risks," he said. "You're not going to order heart biopsies on everybody."

Given this, the field has been "looking more towards imaging-based or biomarker-based screening approaches," he said.

The researchers targeted RBP4 as a potential biomarker for ATTR due to its relationship with the protein transthyretin (TTR). Mutations to TTR can result in misfolding of the protein, which can lead to ATTR. This is particularly a problem for African-Americans, as one TTR mutation, V122I, is presented in 3.4 percent of that population.

In healthy individuals, TTR circulates bound to RBP4. However, the V122I mutation affects TTR's structure and binding properties, which led Ruberg and his colleagues to hypothesize that individuals with mutated TTR proteins might exhibit different levels of RBP4 in their blood.

"We believe that because of the [TTR] mutation, RBP4 doesn't bind very well," he said. And this leads to lower levels of circulating RBP4, as the protein, which normally exists in a stable circulating complex with TTR, is cleared from the blood and excreted in the urine.

"That's why we thought that RBP4 concentration would be a good indicator of TTR instability," Ruberg said.

In a study published last week in JAMA Cardiology, the BUSM team devised a test for ATTR combining measurements of serum RBP4 and TTR along with echocardiograph and electrocardiograph characteristics, and other conventional measures of cardiovascular health that Ruberg said would be available to a physician following standard of care.

Looking at 50 patients with non-amyloid heart failure and cardiac wall thickening, and 25 patients with biopsy-proven ATTR V1221 amyloidosis, the test was able to distinguish between the two groups with an area under the received operating curve of .97. A more streamlined four-parameter model, also including RBP4 concentration, performed with an AUC of .92.

While the study looked at patients with ATTR V1221 amyloidosis, a variety of other TTR mutations have also been implicated in the disease. In fact, Ruberg noted, the majority of ATTR cases stem not from mutated TTR, but from the destabilization of genetically normal forms of the protein.

"Why it destabilizes is not known," he said. "We know certain associations. We know it's associated with being male for some reason. We know it's associated with being white, though that also might be a false observation because we just haven't adequately looked in other populations. But what we call genetically wild-type TTR is actually the most common cause of ATTR amyloidosis, we believe."

If it holds up in larger studies, RBP4 could prove a useful biomarker for these forms of the condition, as well.

It could also help in developing therapies for the condition, Ruberg said, adding that there are a number of drugs for ATTR amyloidosis currently in clinical trials.

"The idea is that if we can figure out a better way to diagnose people, then soon we will have specific therapies for this disease," he said, noting that significant progress in treating the condition has been made in recent years.

"It used to be that doctors would learn that a patient would have amyloidosis and they basically would have a year to live at best," Ruberg said. "That's just not true anymore. Right now, I would say the median survival with wild type or this type, V1221, is on the order of two and a half years, which doesn't sound that great, but we are doing better and better in treating people and learning what works and what doesn't."