B-type natriuretic peptide (BNP) is activated with mitral regurgitation (MR), but it is unclear whether BNP activation is uniform in organic and functional MR and whether it merely reflects symptoms or is a biomarker of left ventricular (LV) geometric and functional alterations. Comprehensive Doppler echocardiography and hormonal measurements were performed prospectively in 99 patients, 50 with organic MR, 28 with functional MR (with similar LV enlargement 130 +/- 21 vs 141 +/- 40, p = 0.18, and age 64 +/- 13 vs 66 +/- 12 years, p = 0.56) and 21 controls subjects of similar age. Compared with the controls, the patients with MR displayed LV remodeling and BNP activation. In those with functional MR compared with those with organic MR, despite a lower regurgitant volume (25 +/- 25 vs 96 +/- 29 ml), higher BNP levels were noted (385 +/- 388 vs 70 +/- 97 pg/ml, p <0.0001), even after stratification by functional class (class I 120 +/- 122 vs 33 +/- 40, class II 318 +/- 470 vs 74 +/- 69, class III to IV 487 +/- 383 vs 268 +/- 165 pg/ml, p = 0.006). The major determinant of BNP activation was the LV end-systolic volume index (p <0.0001), independent of MR etiology, symptoms, other hormonal activation, and hemodynamic characteristics. The BNP level is a biomarker of LV alteration in patients with MR, independent of MR etiology. With BNP >90 pg/ml, the odds ratio of an end-systolic volume index value of >/=60 ml/m(2) was 16 (95% confidence interval 5.5 to 45). In conclusion, BNP activation with MR is more pronounced in those with functional than those with organic MR, even after stratification for functional class, and independently reflects the severity of the LV alteration. Pronounced BNP activation is linked to a higher end-systolic volume index, for which it is a biomarker, irrespective of MR etiology and symptoms.