Is BMI-Adjusted BNP a Real Thing?

Let us set the scene: You have a patient complaining of shortness of breath. The patient gives a poor history, but your spidey sense tells you this is obstructive pulmonary disease vs. new-onset heart failure. His corpulent body habitus is limiting your ability to reliably hear heart or lung sounds. He also has bilateral leg swelling, but he cannot recall if it has been related to his dyspnea. You decide to draw labs, order imaging, and perform an electrocardiogram to help in your decision-making while treating him for possible COPD vs. asthma with nebulizer treatments. The labs all return normal. The radiograph is read as “emphysematous changes and possible mild CHF in appropriate clinical setting”, and your ECG shows only increased voltage to suggest LVH. You could use your sonogram machine to find B-lines and clinch the diagnosis, but the machine is broken, so that is out. You watch the patient continue to have mild respiratory distress as he finishes his second nebulized treatment. You look at the BNP again, and a very normal level of 90 pg/mL stares back at you. You rub your wrinkled forehead and wonder if all that talk about obesity affecting BNP levels actually holds water.

Utility of BNP and NT Pro-BNP

Brain natriuretic peptide (BNP) and N-terminal pro brain natriuretic peptide (NTPBNP) are widely used laboratory tests for establishing or excluding the diagnosis of acute heart failure. The American College of Emergency Physicians recommends this practice by suggesting a cut-off point of 100 pg/mL for BNP as a value below which the likelihood of dyspnea being due to heart failure (HF) is low. They report a sensitivity and specificity of 90% and 70%, respectively (as long as renal dysfunction does not exist). To achieve similar accuracy with NTPBNP, the cut-off is 300 pg/mL.¹ Recent systematic reviews have also found that values below the level of 100 pg/mL are useful for ruling out HF.^2,3 While it is known that renal dysfunction and other conditions (e.g., massive PE) can lead to misinterpretation of BNP and NTPBNP, controversy also exists over the validity of these cut-off values in the setting of obesity. It is becoming increasingly apparent that patients who have excess adipose tissue are more likely to have depressed values compared to individuals who do not. However, it is currently not known by which mechanism this discrepancy occurs. The use of these lab tests to RULE IN HF is a separate topic that will not be discussed here.

So How Does BMI Affect These Things?

Although obesity often accompanies heart failure (HF) it seems that it may also play a protective role decreased morbidity and mortality due to HF being observed among patients with higher BMI.^4,5 It is not known if this protective effect is due to the relative decreased levels of natriuretic peptides. This is of interest to researchers because BNP has been correlated to level of left ventricular wall stress.⁶ However, when subjects were catheterized with a transducer to measure left ventricular pressures in patients with elevated BMI, researchers found that in spite of higher end-diastolic peak pressures, there was a significant inverse relationship between BMI and BNP.⁵ Another study of 600 patients in the emergency department examined BMI and BNP level and found an inverse relationship as well. Each unit that BMI increased made it 8% more likely that their BNP would be <100 pg/mL. It is worthwhile to note that in this study, those patients with higher BMI tended to be younger and had higher creatinine clearance.⁷

A different study took a closer look at adiposity by utilizing dual energy x-ray absorptiometry (now that’s a fancy name!) and showed that there are nuances in this BNP level disparity that go beyond excess adiposity. Where the fat was deposited was an important factor in observed BNP levels. Higher levels of liver fat and possibly visceral fat were associated with decreased levels of natriuretic peptides, while adiposity distributed to the lower body (hips and buttocks) was associated with an increased level. The authors noted that the effects of these adiposity profiles are opposite when it comes to the metabolic syndrome and risk for diabetes.⁸

unknown

How Do I Interpret BNP and NTPBNP in the Overweight Patient?

At this time, there is no consensus for a BMI-adjusted BNP or NTPBNP. It is also unclear if NTPBNP is affected differently than BNP. In addition, differences in natriuretic peptides have been ascribed to lean mass rather than fat mass.^7,9,10 Some researchers suggest both lowering the BNP cut-off value for overweight patients to 54 pg/mL while increasing it to 170 pg/mL for lean patients. By utilizing the area under receiver operating curve they determined that using these cut-offs for subjects with BMI <25 kg/m² and those with BMI >35 kg/m² the utility of BNP would be enhanced. This adjustment would yield a sensitivity of about 90% for the high BMI group while increasing specificity for the lean group. In the same study, the standard 100 pg/mL cut off would have yielded a sensitivity of 77% in overweight subjects and a specificity of only 65% in lean subjects.⁹ Other studies have found that for subjects with CHF and a BMI >25 kg/m² using cut-offs of 125 pg/mL (BNP) and 900 pg/mL (NTPBNP) yielded sensitivities for BNP and NTPBNP that were 80% and 87% respectively.⁷

Bottom Line

A BMI-adjusted BNP/NTPBNP has not yet been widely adopted, however the early data supports its utility. It may also be clinically useful in certain clinical scenarios, such as the one described at the beginning of this article. The post hoc-analysis of the Breathing Not Properly (yup, that spells BNP) trial suggests a cut-off of 54 pg/mL and 170 pg/mL for overweight and lean patients, respectively.⁹ This study included a diverse population in terms of ethnicities and co-morbidities which supports its validity. Just remember, patients with renal dysfunction were excluded in all these studies. In closing, keep an eye on your patient’s BMI when interpreting a “normal” natriuretic peptide level. If the clinical picture fits consider that your patient’s symptoms may indeed due to heart failure despite the non-confirming lab results.

References

1. Silvers SM, Howell JM, Kosowsky JM, Rokos IC, Jagoda AS; American College of Emergency Physicians. Clinical policy: Critical issues in the evaluation and management of adult patients presenting to the emergency department with acute heart failure syndromes. Ann Emerg Med. 2007 May;49(5):627-69. Epub 2007 Apr 3. Review. Erratum in: Ann Emerg Med. 2010 Jan;55(1):16.

2. Martindale JL, Wakai A, Collins SP, Levy PD, Diercks D, Hiestand BC, Fermann GJ, deSouza I, Sinert R. Diagnosing Acute Heart Failure in the Emergency Department: A Systematic Review and Meta-analysis. Acad Emerg Med. 2016 Mar;23(3):223-42. doi: 10.1111/acem.12878. Epub 2016 Feb 13. PubMed PMID: 26910112.

3. Wang CS, FitzGerald JM, Schulzer M, Mak E, Ayas NT. Does this dyspneic patient in the emergency department have congestive heart failure? JAMA. 2005 Oct 19;294(15):1944-56.

4. Horwich T, Hamilton MA, Fonarow GC. B-Type Natriuretic Peptide Levels in Obese Patients With Advanced Heart Failure, Journal of the American College of Cardiology, Volume 47, Issue 1, 3 January 2006, Pages 85-90.

5. Iwanaga Y, Kihara Y, Niizuma S, Noguchi T, Nonogi H, Kita T, Goto Y. BNP in overweight and obese patients with heart failure: an analysis based on the BNP-LV diastolic wall stress relationship. J Card Fail. 2007 Oct;13(8):663-7.

6. Iwanaga Y, Nishi I, Furuichi S, Noguchi T, Sase K, Kihara Y, et al. B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: comparison between systolic and diastolic heart failure. J Am Coll Cardiol 2006;47:742e8.

7. Krauser DG, Lloyd-Jones DM, Chae CU, et al. Effect of body mass index on natriuretic peptide levels in patients with acute congestive heart failure: A ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) substudy, American Heart Journal 2005: 149 (4): 744-750.

8. Neeland IJ, Winders BR, Ayers CR, Das SR, Chang AY, Berry JD, Khera A, McGuire DK, Vega GL, de Lemos JA, Turer AT. Higher natriuretic peptide levels associate with a favorable adipose tissue distribution profile. J Am Coll Cardiol. 2013 Aug 20;62(8):752-60.

9. Daniels LB, Clopton P, Bhalla V, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, Omland T, Storrow AB, Abraham WT, Wu AH, Steg PG, Westheim A, Knudsen CW, Perez A, Kazanegra R, Herrmann HC, McCullough PA, Maisel AS. How obesity affects the cut-points for B-type natriuretic peptide in the diagnosis of acute heart failure. Results from the Breathing Not Properly Multinational Study. Am Heart J. 2006 May;151(5):999-1005.

10. Huang FY, Wang H, Huang BT, Liu W, Peng Y, Zhang C, Xia TL, Wang PJ, Zuo ZL, Heng Y, Liu RS, Pu XB, Gui YY, Chen SJ, Zhu Y, Chen M. The influence of body composition on the N-terminal pro-B-type natriuretic peptide level and its prognostic performance in patients with acute coronary syndrome: a cohort study. Cardiovasc Diabetol. 2016 Apr 6;15:58.