Simplified BMI-stratified diagnostic NT-proBNP thresholds in patients with HFpEF

Background Obesity is associated with lower natriuretic peptide concentrations, potentially reducing the diagnostic accuracy of N-terminal pro–B-type natriuretic peptide (NT-proBNP) for heart failure with preserved ejection fraction (HFpEF). Several body mass index (BMI)–adjusted NT-proBNP thresholds have been proposed, but their performance in large, clinically diagnosed HFpEF populations remains uncertain, particularly according to heart rhythm. Purpose To evaluate the diagnostic performance of guideline-recommended, BMI-adjusted, and recently proposed NT-proBNP thresholds in HFpEF. Methods We analyzed baseline NT-proBNP concentrations in 3,468 participants from the I-Preserve trial, which enrolled patients with a clinical diagnosis of HFpEF defined as a left ventricular ejection fraction ≥45% and NYHA class II-IV functional limitation with hospitalization for HF in the prior 6 months or NYHA class III-IV functional limitation with corroborative evidence (at least one of: chest x-ray evidence of pulmonary congestion; left bundle branch block or left ventricular hypertrophy [LVH] on an electrocardiogram; echocardiographic LVH or left atrial enlargement in the absence of atrial fibrillation [AF]). There were no enrolment restrictions related to BMI or NT-proBNP concentration (investigators were blind to NT-proBNP concentration). We tested guideline-recommended, BMI-adjusted, and recently proposed NT-proBNP thresholds for diagnostic rule-out and rule-in, overall and according to AF status. Results NT-proBNP concentrations declined with increasing BMI. The conventional “rule-out” threshold of 125 pg/mL failed to identify more than one-quarter of patients (130 of 493; 26%) with BMI ≥35 kg/m² who had a clinical diagnosis of HFpEF (Figure 1A). Lower BMI-specific thresholds (50 pg/mL for BMI <35 kg/m² and 35 pg/mL for BMI ≥35 kg/m²) identified over 90% of HFpEF cases in patients in sinus rhythm (Figure 1B). In contrast, in patients with AF, >95% exceeded all rule-out thresholds (Figure 1C). When considering both the recently proposed “rule-in” and “rule-out” thresholds (Figure 1D), values falling between these thresholds were classified as an “indeterminate zone,” in which patients may require exercise testing to confirm or refute a diagnosis of HFpEF. Of the patients in sinus rhythm, 60% and 48% of those with a BMI of <35 kg/m2 and ≥35 kg/m2, respectively, fell into the “indeterminate zone”, whereas the corresponding proportions for those in AF were 12% and 4% (Figure 1D). Conclusions BMI-specific NT-proBNP rule-out thresholds substantially improve diagnostic sensitivity for HFpEF in patients in sinus rhythm. In patients with AF, substantially higher rule-in thresholds are required, although current cut-points may still misclassify a meaningful proportion of patients. These findings support reconsideration of natriuretic peptide–based diagnostic pathways incorporating BMI and heart rhythm-specific thresholds.