A simple blood test to detect plasma levels of the vitamin-A transport protein retinol-binding protein 4 (RBP4) could help identify patients with transthyretin cardiac amyloidosis (ATTR) -- an under-recognized cause of heart failure seen mostly in older, African Americans.
A prediction model involving circulating plasma RBP4 with standard-of-care diagnostic markers was shown to be highly accurate for identifying African-American heart failure patients with ATTR.
If the results of the new study are validated in larger studies, researchers say the model could be a useful tool to determine if patients at risk for ATTR should undergo further diagnostic testing.
"The test may have clinical utility as a first-line screening test for the disease in elderly African-American individuals with heart failure, guiding clinical decision-making," , of Boston University School of Medicine, and colleagues, wrote online in .
Around 3.5% of African Americans carry the genetic mutation that is prevalent in familial TTR amyloidosis, but the mutation appears to be generally absent in Caucasians.
"Unfortunately, identification generally occurs after the development of symptoms, and a large number of cases are misdiagnosed or underdiagnosed," the researchers wrote.
In an interview with 鶹ý, Ruberg explained that the recent development of targeted treatments for ATTR led to the search for simpler ways of diagnosing heart failure caused by TTR amyloidosis.
The drug (Vyndaqel, Pfizer), which is approved in Europe and is in clinical trials in the U.S., selectively binds to TTR.
"These new treatments won't cure patients, but the hope is that they will extend life by keeping the illness at bay," Ruberg said.
He and his colleagues studied RBP4 because animal and in vitro studies have suggested that diminished levels of the binding protein may cause TTR misfolding: "We sought to determine the utility of circulating RBP4 as a tool to identify ATTR V122I amyloidosis in a cohort of elderly African-American patients with heart failure. We further aimed to develop a clinical prediction model for ATTR V122I amyloidosis based on clinical, echocardiographic, and electrocardiographic characteristics, along with RBP4 and other cardiac biomarkers."
The combined prospective and retrospective cohort study included 50 African-American patients who were age 60 or older with non-amyloid heart failure and cardiac wall thickening prospectively genotyped and a comparator cohort of 25 patients with biopsy-proven ATTR amyloidosis.
The two groups had similar characteristics. The mean age was 72.2 (standard deviation [SD] of 7.4) years and 69.2 (5.7) years, respectively, for the amyloidosis and control patients.
Serum RBP4 concentration was lower in patients with ATTR amyloidosis compared with non-amyloid controls (31.5 versus 49.4 μg/mL, P<0.001), and the difference persisted after controlling for potential confounding variables.
Left ventricular ejection fraction was lower in patients with ATTR V122I amyloidosis (mean 40% [SD 14%] versus 57% [SD 14%], P<0.001), but interventricular septal diameter was higher (mean 16 [SD 3] versus 14 [SD 2] mm, P<0.001).
Receiver operating characteristic (ROC) analysis identified RBP4 as a sensitive identifier of ATTR V122I amyloidosis -- area under the curve (AUC)=0.78; 95% CI, 0.67-0.88.
A clinical prediction algorithm composed of RBP4, TTR, left ventricular ejection fraction, interventricular septal diameter, mean limb lead QRS voltage, and grade 3 diastolic dysfunction yielded "excellent discriminatory capacity" for ATTR V122I amyloidosis (AUC=97, 95% CI, 0.93-1.00), the researchers reported.
A four-parameter model, including RBP4 concentration, retained excellent discrimination (AUC=0.92, 95% CI, 0,86-0.99).
"To our knowledge, this association has not been previously reported in the clinical setting, but in vitro disease models have found a potential role of RBP4 in stabilizing TTR and preventing misfolding," Ruberg and colleagues wrote.
"We found that an RBP4 concentration greater than or equal to 50 μg/mL had 100% sensitivity (but modest specificity) and provided 100% negative predictive value in excluding ATTR V122I amyloidosis without the need for further testing (similar in the way that D-dimer concentration is used to exclude venous thromboembolism), suggesting a potential utility of RBP4 concentration as an initial screening test."
Study limitations noted by the researchers included the relatively small number of patients, and the exclusion of non-African Americans and younger patients, which limited generalizability.
The team characterized the findings as "promising but preliminary."
"Although the prediction rule performance estimates remained excellent in a small replication cohort, external validation in a larger, independent patient population will be necessary before widespread clinical adaption," the researchers concluded.
Disclosures
This research was funded by the National Institutes of Health and the Young Family Amyloid Research Fund.
The researchers reported having no relevant relationships with industry.
Primary Source
JAMA Cardiology
Arvanitis M, et al "Identification of transthyretin cardiac amyloidosis using serum retinol-binding protein 4 and a clinical prediction model" JAMA Cardio 2017; DOI: 10.1001/jamacardio.2016.5864.