FBS Colloquia No.418Laboratory of Medical Biochemistry

Relative Natriuretic Peptide Deficiency Reveals a Hidden and Reversible Cardiometabolic Vulnerability Before HFpEF

Relative natriuretic peptide (NP) deficiency, defined as an inappropriately blunted NP response relative to cardiac load, is often observed in obesity-associated HFpEF, but its biological significance remains unclear. We analyzed 102 asymptomatic individuals with fasting cardiac ^18F-FDG PET/CT, echocardiography, and NT-proBNP, and identified a subgroup with high myocardial FDG uptake despite uniformly low NT-proBNP. To examine the pathophysiological significance of this phenotype, we studied CR9 enhancer-deleted mice with impaired stress-inducible NP expression. Under chow feeding, these mice showed increased myocardial FDG uptake, reduced cGMP–PKG signaling, and cardiac lipid accumulation, while ATP levels remained preserved, indicating a compensated but vulnerable metabolic state. In complementary cultured cardiomyocyte experiments, CRISPRi and fatty acid tracing suggested that NP deficiency impairs mobilization of stored neutral lipids, supporting a role for defective lipid droplet utilization in this metabolic vulnerability. Under high-fat diet stress, the compensated state collapsed, resulting in ATP depletion and severe diastolic dysfunction with preserved ejection fraction. Moreover, the sGC stimulator vericiguat improved the metabolic and diastolic abnormalities during the compensated phase. These findings suggest that relative NP deficiency defines a preclinical cardiometabolic vulnerability before overt HFpEF and that this state is at least partly reversible through cGMP pathway augmentation.