By Jamie L. W. Kennedy, MD, FACC
Associate Professor, Division of Cardiology, Advanced Heart Failure & Transplant Cardiology, University of California, San Francisco
SYNOPSIS: In patients with clinical heart failure and low B-type natriuretic peptide levels, the authors found these patients usually are young and obese, with higher ejection fraction and better renal function.
SOURCE: Bachmann KN, Gupta DK, Xu M, et al. Unexpectedly low natriuretic peptide levels in patients with heart failure. JACC Heart Fail 2021;9:192-200.
The myocardium releases natriuretic peptides in response to elevated wall stress. There are two forms: atrial natriuretic peptide (ANP) and brain, or B-type, natriuretic peptide (BNP). They exert their effects in several ways, including increasing renal sodium and water excretion, promoting vasodilation, and reducing myocardial fibrosis.
Clinical use of BNP levels started with evaluation of patients in the ED for dyspnea in the Breathing Not Properly trial.1 They have become powerful tools for risk assessment, not only in heart failure but also patients with atrial fibrillation, pulmonary arterial hypertension, acute pulmonary embolism, and systemic hypertension. Serial BNP measurements can help track disease course over time. BNP levels are increasingly incorporated into clinical trial criteria as well to enrich the study population in patients at high risk for clinical events. For example, some heart failure therapy trials have required BNP levels above a certain threshold before enrollment. BNP has become a therapeutic target, too; sacubitril inhibits neprilysin, resulting in higher levels of natriuretic peptides.
Interestingly, there is a subset of patients with clear heart failure with normal or even low BNP values. To further evaluate this phenomenon, Bachmann et al queried a de-identified version of their institution’s electronic medical record to find patients with measured BNP values and heart failure based on echo or hemodynamic criteria or hospitalized with heart failure. Echo criteria included left ventricular ejection fraction 35% or lower or left ventricular hypertrophy based on estimated left ventricular mass (> 162 g for women, > 224 g for men). BNP measurement was required within 90 days of the study. Hemodynamic criteria included left ventricular end-diastolic pressure, pulmonary capillary wedge pressure, or right atrial pressure of 20 mmHg or greater or cardiac index less than 2 L/min/m2, with BNP measurements required within one day of the procedure. Heart failure hospitalizations required at least one dose of IV diuretic and an ICD diagnosis code for heart failure, and that the BNP measurement was recorded in the 24 hours preceding admission or during the hospitalization. The authors identified 47,970 adult patients with a measured BNP value: 9,153 were associated with a heart failure hospitalization, 7,041 met echo criteria, and 363 met hemodynamic criteria (some patients fell into multiple groups). BNP levels below 50 pg/mL were present in 4.9% of patients hospitalized for heart failure, 14% of patients with abnormal echoes, and 16.3% of patients with abnormal hemodynamics.
Bachmann et al studied the characteristics of patients hospitalized with heart failure, looking for differences between patients with low (< 50 pg/mL) vs. normal or elevated BNP levels. In a multivariate analysis, higher BMI, younger age, higher ejection fraction, and lower creatinine predicted low BNP levels. Finally, the authors sequenced whole exomes for nine patients with low BNP levels (less than 10 pg/mL to 37 pg/mL). They did not find any loss of function variants in the synthetic pathway for BNP production or mutations that would prevent accurate measurement of BNP levels in lab assays. They found two loss-of-function variants in the NP clearance receptor; one would expect this to result in higher BNP levels. These findings suggest up to 16% of patients with significant hemodynamic derangements produce normal BNP values, and the data confirm the previously observed trend: lower BNPs are seen in younger patients with higher BMIs, higher ejection fraction, and lower creatinine levels.
The heart failure hospitalization criteria are the most subjective. Patients with dyspnea and low BNP levels may be erroneously diagnosed with something other than heart failure and inappropriately treated. Thus, they were not captured in this study. The timing of BNP measurement during hospitalization also is relevant. A normal BNP at admission would be surprising, while a normal BNP at discharge may be a marker of aggressive heart failure management. The authors’ analysis did not include this consideration.
The authors accepted a surprisingly wide period between BNP measurement and echo study. Unfortunately, this was a significant limitation of their study. It is not uncommon for cardiac function to change dramatically over a 90-day period. For example, an acute myocardial infarction or stress cardiomyopathy often exhibit marked improvement in left ventricular function within days of hospitalization, making interpretation of widely spaced echo and BNP results difficult at best. The hemodynamically defined patients are the most compelling. Significantly elevated filling pressures or low cardiac index closely correlated with BNP measurements.
Management of obese patients with heart failure can be challenging. Assessment of volume status by physical exam is limited: neck veins can be hard to visualize, hepatomegaly hard to appreciate, and peripheral edema from venous stasis is common. As demonstrated in this study, BNP levels can be low, too, taking away another diagnostic tool. Implantable pulmonary artery pressure sensors can be helpful, although patients with large chest circumferences are not candidates for this device. Further compounding the problem: Obese patients are more likely to be excluded from clinical trials based on low BNP levels, limiting our understanding of heart failure therapies in this significant patient population.
- Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161-167.