The natriuretic peptides (NP) –primarily B-type NP (BNP) and N-terminal pro-BNP—have earned a solid place in diagnosing and predicting outcomes in heart failure. However, researchers have been actively exploring other NPs that might be more stable than BNP while providing equally significant clinical information. In one recent study, investigators examined the influence of demographic variables on the interpretation of mid-regional pro atrial NP in heart failure, findings covered in this issue of Strategies.

The natriuretic peptides (NP), which are released by cardiomyocytes in response to stretch, have proven useful in diagnosing and predicting outcomes in heart failure. While most of the evidence in this realm involves B-type NP (BNP) and N-terminal pro-BNP, clinical interest in the role of other NPs is high. One of the more promising is mid-regional pro atrial NP (MR-proANP). As part of the Biomarkers in Acute Heart Failure (BACH) study, a 15-center international consortium of researchers recently evaluated how demographic variables affect interpretation of this biomarker (Eur J Heart Fail 2012; 14:22-31).

“Our paper was a sub-study of the BACH trial, which evaluated several new biomarkers to help with diagnosis and prognosis in patients presenting to the emergency department with shortness of breath,” explained the study’s lead investigator, Lori Daniels, MD. “We were trying to understand how levels vary based on an individual’s age, race, sex, and body mass index, because we know from other biomarkers that we use, these demographic variables can affect levels of the biomarkers and also how to interpret them. It’s important that doctors who are using this test understand which factors intrinsic to the patient can affect its blood levels.” Daniels is associate professor of medicine at the University of California San Diego and associate director of the cardiac care unit at the UCSD Sulpizio Cardiovascular Center in La Jolla.

The study involved 1,352 individuals who presented to the emergency department with a primary complaint of shortness of breath. All patients were at least 18 years old, did not have acute ST-elevation myocardial infarction, and were not on dialysis. Their mean age was 63 years and mean body mass index (BMI) was 29.1. Overall, 37% of patients received an adjudicated diagnosis of acute heart failure by two cardiologists who had been blinded to the investigational biomarkers, the emergency physicians’ diagnoses, and to each other’s assessments. The diagnosis of heart failure differed significantly by age group, race, sex, and BMI group.

After a series of statistical analyses, the researchers found that age, sex, race, and BMI affect MR-proANP levels to varying degrees. MR-proANP levels increased with age regardless of whether patients had heart failure. However, after adjusting for other variables, MR-proANP levels did not differ significantly by age group in those with a final diagnosis of heart failure. In terms of race, MR-proANP levels in blacks without heart failure were lower than in whites, but the reverse was true among blacks with diagnosed heart failure. These differences persisted after adjustment for other variables. Regardless of whether they had heart failure, men had slightly higher levels of MR-proANP than women; after adjustment for other variables, this difference remained significant only in those with a final diagnosis of heart failure. In all patients, MR-proANP levels decreased as BMI increased, but after adjustment for other variables, MR-proANP predicted heart failure equally across all BMI groups.

Based on their analyses, the investigators found a cutpoint of 120 pmol/L to be 90% sensitive in ruling out a diagnosis of acute heart failure in all subgroups, except white subjects younger than age 50. The authors suggested that to optimize sensitivity, lower cutoffs might be considered in patients with high BMIs and in those younger than 50 years old. “The take home point is that 120 pmol/L is still a good number to remember, but similar to BNP, the numbers tend to be a little lower in people who are obese and probably because of clinical reasons, younger patients tend to have lower numbers. They have fewer comorbidities, leading to lower levels of MR-proANP,” said Daniels.

Allan Jaffe, MD, welcomed the study findings and predicted that this type of work might forestall some challenges that initially had been associated with interpreting BNP results. “When BNP first hit the market, there was the thought that one would just need to use this particular magic cutoff and all would be well. But as clinicians got more involved and realized the complexity of some of these things, many people became disappointed with the performance of the assays and with their ability to use BNP results intelligently,” he recalled. “This is the sort of paper that’s relatively important in the sense that it took a long time to fix the problem with BNP and NTpro-BNP, and now researchers are having to go back, reanalyze the data and put some important caveats into the thinking about these markers. So here the authors are trying to really get into those issues, and from that perspective they’re learning from the past so that with this marker, MR-proANP, we don’t end up with the same problem.” Jaffe is a professor of medicine, consultant in cardiology and laboratory medicine, and chair of clinical core laboratory services at Mayo Clinic in Rochester, Minn.

Daniels explained that while BNP, NT-pro BNP, and MR-proANP all reflect myocyte stress associated with heart failure, they also may respond to slightly different pathophysiologies. In addition, the midregional epitopes of prohormones may be more stable to degradation than epitopes in the N- or C-terminus. This suggests that MR-proANP measurements eventually might provide not only complementary but also independently additive information to that derived from BNP or NT-pro BNP. “We believe that most BNP and NT-proBNP is probably from left ventricular stretch, although some of it is atrial, whereas ANP is probably more reflective of the atria. The exact intricacies are quite complicated, but they each have different half-lives, renal dependencies, and the like,” she explained.

Daniels added that MR-proANP might help clarify situations in which BNP is difficult to interpret. For example, BNP levels <100 pg/mL have a high negative predictive value in ruling out heart failure, whereas levels >500 pg/mL are likely to indicate heart failure. However, in patients with BNP levels ≥100 pg/mL or ≤500 pg/mL and equivocal symptoms, BNP results do not provide as clear a picture.

Jaffe suggested that physicians might use MR-proANP and BNP results in a complementary way, but under a different set of clinical circumstances. “My own guess is that for straightforward heart failure, they may not be terribly different, and I’m not convinced that they’ll be critical in that sort of middle zone of BNP values between 100 and 500 pg/mL,” he said. “However, there’s a lot of valvular heart disease that has differential atrial versus ventricular components. An example is mitral regurgitation, in which there is substantial atrial involvement but over time ventricular involvement develops as the left ventricle dilates. It may well be that there are differential effects from one marker versus the other, and my guess is that over time we’ll be able to use them synergistically.”

As Daniels, her BACH colleagues, and other researchers continue to peel back the layers of complexity from MR-proANP, both she and Jaffe encouraged laboratorians to stay tuned. “There’s so much data from this BACH trial still being explored, in patients with diabetes, with atrial fibrillation, and a lot of other subcategories. We also want to see replication of our results in other studies,” she said. “Ultimately, I’m sure people interested in population-based studies will do more work with it and that’s starting to be done as well.”