Natriuretic peptides during the development of doxorubicin-induced left ventricular diastolic dysfunction

Objectives. To investigate changes in plasma atrial natriuretic peptide (ANP), N-terminal pro-atrial natriuretic peptide (NT-pro-ANP) and brain natriuretic peptide (BNP) during the development of doxorubicin-induccd left ventricular systolic and diastolic dysfunction as measured by echocardiography (ECHO). Design. Prospective study. Setting. University hospital. Subjects. Twenty-eight adult patients with non-Hodgkin's lymphoma, who received doxorubicin to the cumulative dose of 400-500 mg m(-2). Main outcome measures. The relationship between plasma natriuretic peptides and systolic and diastolic ECHO indices after the cumulative doxorubicin doses 2 of 200, 400 and 500 mg m(-2). Results. Left ventricular ejection fraction (LVEF, by 2D ECHO) decreased from 58 +/- 1.7 to 52.5 +/- 1.3% (P = 0.036) and fractional shortening (FS) from 34.6 +/- 1.4 to 27.8 +/- 0.9% (P = 0.002). Peak E wave velocity decreased from 63.3 +/- 3.2 to 51.3 +/- 2.6 cm. s(-1) (P = 0.008) resulting in a statistically nonsignificant decrease in E/A ratio from 1.08 +/- 0.01 to 0.85 +/- 0.07. A significant decrease was observed in the percentage of left ventricular filling during the 1/3 of diastole (1/3FF) from 42.2 +/- 1.7 to 36.5 +/- 2.0% (P < 0.001). LV end systolic diameter increased from 32 ± 1 to 38 ± 1 min (P = 0.011), whereas left atrial (LA) diameter remained unchanged. Peak rifling rate decreased from 4.4 ± 0.2 to 4.0 ± 0.2 stroke volume s(-1) (SV s(-1)) (ns). Plasma levels of ANP increased from 16.4 ± 1.3 to 22.7 ± 2.4 pmol L-1 (P = 0.002), NT-pro-ANP from 288 22 to 380 ± 42 pmol L-1 (P = 0.019) and BNP from 3.3 ± 0.4 to 8.5 ± 2.0 pmol L-1 (P = 0.020). There was a significant inverse correlation between the decrease in FS and the increases in plasma NT-pro-ANP (r = -0.524, P = 0.018) and plasma BNP (r = 0.462, P = 0.04) and between the decrease in PFR and the increases in plasma ANP (r = -0.457, P = 0.043) and plasma NT-pro-ANP (r = -0.478, P = 0,033). Furthermore, after doxorubicin therapy, significant inverse correlations were observed between E/A ratio and plasma ANP (r = -0.535, P = 0.008), between E/A ratio and plasma NT-pro-ANP (r = -0.432, P = 0.04) and between E/A ratio and plasma BNP (r = -0.557, P = 0.006) as well as between 1/3FF and plasma BNP (r = -0.493, P = 0.017). There was also a trend for correlation between LA diameter and plasma BNP (r = 0.395, P = 0.062) and peak E wave velocity and plasma BNP (r = -0.414, P = 0.05), respectively. However, no significant correlations were observed between any of the systolic parameters and natriuretic peptide levels. Conclusions. The results of this prospective study show that during the evolution of doxorubicin-induced LV dysfunction the secretion of natriuretic peptides is more closely associated with the impairment of left ventricular diastolic filling, than with the deterioration of LV systolic function.