Natriuretic peptides during the development of doxorubicin‐induced left ventricular diastolic dysfunction
Authors: Nousiainen T. , Vanninen E. , Jantunen E. , Puustinen J. , Remes J. , Rantala A. , Vuolteenaho O. , Hartikainen J. 
Published: March 2003

Abstract. Nousiainen T, Vanninen E, Jantunen E, Puustinen J, Remes J, Rantala A, Vuolteenaho O, Hartikainen J (Kuopio University Hospital, Kuopio; Satakunta Central Hospital, Pori; University of Oulu, Oulu, Finland). Natriuretic peptides during the development of doxorubicin‐induced left ventricular diastolic dysfunction. J Intern Med 2002; 251: 228–234.

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‐induced 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 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 mm (P=0.011), whereas left atrial (LA) diameter remained unchanged. Peak filling 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.