Rethinking Biomarker Thresholds: Why Current NT-proBNP Cutoffs Fail Patients with Obesity and HFpEF

The Diagnostic Dilemma: When Biomarkers and BMI Collide

In the landscape of modern cardiology, natriuretic peptides—specifically N-terminal pro-B-type natriuretic peptide (NT-proBNP)—serve as the cornerstone for diagnosing and risk-stratifying heart failure (HF). Guidelines from major societies, including the American Heart Association and the European Society of Cardiology, rely heavily on these biomarkers to confirm clinical suspicion and determine eligibility for life-saving clinical trials. However, a persistent confounding factor has long troubled clinicians: the inverse relationship between body mass index (BMI) and circulating natriuretic peptide levels.

While it is well-established that patients with higher adiposity tend to have lower NT-proBNP levels, the clinical impact of this phenomenon on risk prediction has remained unclear. Does a ‘normal’ NT-proBNP in an obese patient carry the same prognostic weight as it does in a lean patient? A landmark study by Ostrominski et al., published in the Journal of the American College of Cardiology, provides a definitive answer, suggesting that our current ‘one-size-fits-all’ approach to biomarkers may be systematically disadvantaging patients with obesity.

The Pooled Analysis: A High-Power Investigation into HFmrEF and HFpEF

To investigate this issue, researchers conducted a participant-level pooled analysis of four global, randomized outcomes trials: I-PRESERVE, TOPCAT, PARAGON-HF, and DELIVER. This robust dataset included 14,750 participants with heart failure and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). This specific population is particularly relevant because obesity is a primary driver of the HFpEF phenotype, often characterized by systemic inflammation and metabolic dysfunction.

The study population was diverse, with a mean age of 72 years and an equal split between male and female participants. The mean BMI was 30 kg/m2, reflecting the high prevalence of overweight and obesity in the HFpEF population. The primary objective was to evaluate the association between NT-proBNP and clinical outcomes—including cardiovascular death and HF hospitalization—across the full spectrum of BMI.

Key Findings: The Inverse Relationship Between Adiposity and Natriuretic Peptides

The analysis confirmed a significant and nonlinear inverse association between baseline BMI and NT-proBNP levels. As BMI increased, the median NT-proBNP levels decreased, even when controlling for the severity of cardiac dysfunction. This confirms the ‘obesity paradox’ of natriuretic peptides: those who are often the most symptomatic and at the highest risk for metabolic complications may present with the lowest biomarker signals.

Over a median follow-up of 2.8 years, the researchers found that while a doubling of NT-proBNP was associated with a 40% higher rate of cardiovascular death or HF hospitalization (HR: 1.40; 95% CI: 1.36-1.43), this association was not uniform across all weight classes. Specifically, the association between the biomarker and clinical outcomes appeared incrementally blunted as BMI increased (P-interaction = 0.008). This suggests that in the presence of high adiposity, NT-proBNP becomes a less sensitive ‘barometer’ of absolute risk.

Quantifying the Inequity: Why Fixed Thresholds Fail

The most striking finding of the study relates to the absolute risk levels. For a patient to have an absolute risk of 5 events per 100 person-years (a common benchmark for high risk), the required NT-proBNP level varied drastically based on BMI. In participants without atrial fibrillation, the threshold for this risk level was nearly 3-fold lower in those with a BMI ≥35 kg/m2 (158 pg/mL) compared to those with a BMI <35 kg/m2 (450 pg/mL).

Furthermore, when looking at contemporary NT-proBNP-based trial eligibility thresholds, the researchers discovered a significant disparity in actual risk. Among persons with a BMI <30 kg/m2, the absolute risk of adverse outcomes was 3.5 per 100 person-years. In contrast, among those with a BMI ≥40 kg/m2, the risk at the same biomarker threshold was 7.3 per 100 person-years. Effectively, we are requiring obese patients to be twice as 'sick' or at twice the risk before they meet the criteria for diagnosis or trial enrollment.

Mechanistic Insights: The Biological Basis of the Suppression

The suppression of natriuretic peptides in obesity is likely multifactorial. Biologically, adipose tissue expresses high levels of natriuretic peptide clearance receptors (NPR-C), which physically remove the peptides from circulation. Additionally, there is evidence that the ‘neprilysin’ enzyme, which breaks down active peptides, may have altered activity in obese individuals. Beyond clearance, there is an ‘impaired synthesis’ hypothesis, where metabolic syndrome and insulin resistance suppress the release of these peptides from the myocardium despite high intracardiac pressures. This creates a state of ‘natriuretic peptide deficiency,’ which may further exacerbate sodium retention and hypertension in obese patients.

Clinical Implications: Transforming Trials and Practice

The implications of this study are profound for both clinical practice and the design of future clinical trials. If we continue to use fixed NT-proBNP thresholds, we are likely under-diagnosing HFpEF in patients with obesity, leading to delays in initiating evidence-based therapies such as SGLT2 inhibitors or MRAs.

1. Redefining Trial Eligibility

Many HFpEF trials require an NT-proBNP level of ≥200 or ≥300 pg/mL for enrollment. Based on this data, these thresholds systematically exclude a large cohort of high-risk obese patients. Future trials should consider BMI-indexed entry criteria to ensure that the study populations truly reflect the risk profile of the real-world HF population.

2. Diagnostic Calibration

For clinicians in the outpatient setting, a ‘low’ NT-proBNP in a patient with a BMI of 40 kg/m2 should be interpreted with extreme caution. It does not rule out heart failure with the same certainty that it might in a lean patient. Incorporating imaging (such as diastolic stress echo) or invasive hemodynamics may be necessary when clinical suspicion remains high despite modest biomarker elevations.

Expert Commentary and Limitations

Experts note that while this study provides a clear mandate for change, implementing BMI-adjusted thresholds in clinical practice requires careful standardization. There is a risk of over-diagnosis if thresholds are set too low, potentially leading to unnecessary treatments. Furthermore, BMI is a surrogate for adiposity; future research should investigate whether waist circumference or body composition measures (like lean vs. fat mass) provide even better calibration for biomarker interpretation.

The study’s strength lies in its large, well-characterized population from landmark trials. However, it is important to remember that these were trial participants, who may be healthier than the ‘average’ patient seen in community practice. Additionally, the data primarily focused on NT-proBNP; while BNP follows similar patterns, the exact numerical adjustments may differ.

Conclusion: Toward Personalized Biomarker Medicine

The study by Ostrominski and colleagues marks a pivot point in our understanding of heart failure diagnostics. By demonstrating that current NT-proBNP thresholds substantially underestimate the risk in obese individuals, the research challenges the utility of fixed cutoffs. As we move toward a more personalized approach to cardiovascular medicine, accounting for a patient’s metabolic profile is no longer optional—it is a clinical necessity to ensure equitable and accurate care for the growing population of patients with obesity and heart failure.

Funding and Clinical Trial Registration

This analysis was supported by various grants and pooled data from the following trials: I-PRESERVE (NCT00095238), TOPCAT (NCT00094302), PARAGON-HF (NCT01920711), and DELIVER (NCT03619213).

References

1. Ostrominski JW, et al. Natriuretic Peptides, Body Mass Index, and Clinical Outcomes in Heart Failure With Mildly Reduced or Preserved Ejection Fraction. J Am Coll Cardiol. 2025;86(20):1823-1839.

2. McDonagh TA, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599-3726.

3. Heidenreich PA, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2022;79(17):e263-e421.