NPPA encodes atrial natriuretic peptide (ANP), a cardiac hormone with primary endocrine and paracrine functions in cardio-renal homeostasis 1. ANP is produced predominantly by atrial cardiomyocytes and secreted in response to cardiac stress 2. The peptide signals through transmembrane guanylyl cyclase receptors (NPR-A), activating cGMP-dependent pathways that mediate natriuresis, vasodilation, and reduced blood pressure and cardiac hypertrophy 3. NPPA expression is tightly regulated: normally suppressed in adult ventricular myocardium but strongly upregulated during cardiac stress and heart failure 2. Dysregulation of NPPA contributes to pathological cardiac remodeling; inhibition of NEU1-GATA4 interaction reduces pathological NPPA/NPPB activation during hypertrophy 4, while GATA4 overexpression suppresses NPPA expression in heart failure with preserved ejection fraction 5. Clinically, NPPA variants associate with hypertension susceptibility—the rs5063 SNP correlates with altered ANP levels and hypertension risk 6—and with preeclampsia through effects on blood pressure regulation and placental remodeling 7. Plasma ANP levels serve as diagnostic and prognostic biomarkers for heart disease 1. Aberrant enhancer-promoter connectivity in DCM hearts promotes cotranscription of NPPA/NPPB 8, highlighting the gene's central role in cardiac pathophysiology.