title: Neuroendocrine changes during the evolution of doxorubicin-induced left ventricular dysfunction in adult lymphoma patients.
abstract: Doxorubicin-induced cardiotoxicity was used as a model to prospectively investigate neuroendocrine changes during the development of left ventricular dysfunction. Radionuclide ventriculography, frequency domain analysis of heart rate variability (HRV), and plasma noradrenaline and natriuretic peptide measurements were performed in 27 adult lymphoma patients at baseline and after cumulative doxorubicin doses of 200, 400 and 500 mg/m(2). The left ventricular ejection fraction (LVEF) decreased from 58.1+/-1.4% to 50.3+/-1.1% (P<0.001) and 49.3+/-1.7% (P<0.001) after cumulative doxorubicin doses of 400 and 500 mg/m(2) respectively. With a doxorubicin dose of up to 400 mg/m(2) there was an increase in sympathetic tone, characterized by a decrease in the normalized high-frequency (HF(nu)) power (P=0.011), and increases in the normalized low-frequency (LF(nu)) power (P=0.011), the LF/HF ratio (P=0.021) and the plasma noradrenaline concentration (P=0.034). The decrease in LVEF was correlated with the changes in LF(nu) and HF(nu) power (r=0.540, P=0.012) and LF/HF ratio (r=-0.452, P=0.04). However, after the cumulative doxorubicin dose of 500 mg/m(2) the changes in HRV components and plasma noradrenaline levels returned towards baseline. This was accompanied by increased concentrations of plasma atrial natriuretic peptide (P=0.004) and brain natriuretic peptide (P=0.021). Our findings suggest that doxorubicin-induced left ventricular dysfunction is associated with an early change in sympathovagal balance towards sympathetic predominance. Along with further progression of left ventricular dysfunction, there is an attenuation of sympathetic tone, which may be attributable to sympatho-adrenal inhibition by increased secretion of natriuretic peptides.
authors.affiliation: Department of Medicine, Kuopio University Hospital, P.O.B. 1777, 70211 Kuopio, Finland. tapio.nousiainen@kuh.fi
authors.forename: T
authors.initials: T
authors.lastname: Nousiainen
authors.forename: E
authors.initials: E
authors.lastname: Vanninen
authors.forename: E
authors.initials: E
authors.lastname: Jantunen
authors.forename: J
authors.initials: J
authors.lastname: Remes
authors.forename: E
authors.initials: E
authors.lastname: Ritanen
authors.forename: O
authors.initials: O
authors.lastname: Vuolteenaho
authors.forename: J
authors.initials: J
authors.lastname: Hartikainen
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D009320:Atrial Natriuretic Factor / Q000097:blood; D001341:Autonomic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D003520:Cyclophosphamide / Q000009:adverse effects / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D009638:Norepinephrine / Q000097:blood; D011241:Prednisone / Q000009:adverse effects / Q000627:therapeutic use; D011446:Prospective Studies; D015635:Radionuclide Ventriculography; D013318:Stroke Volume / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000139:chemically induced* / Q000503:physiopathology; D014750:Vincristine / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D000903:Antibiotics, Antineoplastic; D020097:Natriuretic Peptide, Brain; D014750:Vincristine; D004317:Doxorubicin; D009320:Atrial Natriuretic Factor; D003520:Cyclophosphamide; D011241:Prednisone; D009638:Norepinephrine