title: Fluorouracil induces myocardial ischemia with increases of plasma brain natriuretic peptide and lactic acid but without dysfunction of left ventricle.
abstract: OBJECTIVE
  Fluorouracil (FU) is a cornerstone of colorectal cancer treatment; however, it has clinical and subclinical influence on the heart. This study aimed to clarify the pathophysiology, risk factors, and long-term effects of FU cardiotoxicity.
  
  
  METHODS
  The study prospectively accrued colorectal cancer patients (n=106) completely resected and adjuvantly treated with FU and oxaliplatin according to the FOLFOX4 regimen (infusional FU, folinic acid, and oxaliplatin). Serial measurements were made of systolic and diastolic features of the left ventricle by radionuclide ventriculography, plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), lactic acid, and ECG before chemotherapy, immediately after a treatment infusion, and at follow-up 2 weeks after cessation of the intended 12 treatment courses and were further evaluated by multivariate regression analysis that included cardiovascular history and its risk factors.
  
  
  RESULTS
  In the entire cohort, NT-proBNP significantly increased from baseline 14.5±3.2 pmol/L (mean±standard error) to 28.3±5.3 pmol/L during FU therapy (P<.001). Nine patients (8.5%) with cardiotoxicity had significantly higher NT-proBNP of 55.3±40.8 pmol/L compared with 25.4±4.1 pmol/L in those without (P<.001). In multivariate analysis, the FU-induced rise of NT-proBNP was significantly higher in females (P<.001). Plasma lactic acid significantly increased from baseline (1.3±0.1 mmol/L to 1.8±0.1 mmol/L) during FU therapy (P<.001). Left ventricular ejection fraction at baseline of 0.66±0.01 remained unchanged at 0.65±0.01 during FU therapy and 0.66±0.01 at follow-up (P=.4).
  
  
  CONCLUSIONS
  FU therapy generally induces myocardial neuroendocrine changes with increasing plasma NT-proBNP and lactic acid but without long-term dysfunction of the left ventricle. The usability of NT-proBNP as a predictive marker for FU cardiotoxicity remains to be clarified.
authors.affiliation: Rigshospitalet, Copenhagen University Hospital, and Department of Oncology 5073, University of Copenhagen, 9 Blegdamsvej, Copenhagen, DK-2100, Denmark. soren.a.jensen@mail.tele.dk
authors.forename: Søren Astrup
authors.initials: SA
authors.lastname: Jensen
authors.forename: Philip
authors.initials: P
authors.lastname: Hasbak
authors.forename: Jann
authors.initials: J
authors.lastname: Mortensen
authors.forename: Jens Benn
authors.initials: JB
authors.lastname: Sørensen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000601:surgery; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects*; D006801:Humans; D019344:Lactic Acid / Q000097:blood*; D002955:Leucovorin / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000139:chemically induced* / Q000503:physiopathology; D020097:Natriuretic Peptide, Brain / Q000097:blood*; D009944:Organoplatinum Compounds / Q000009:adverse effects; D011446:Prospective Studies; D012307:Risk Factors; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
chemical_list: D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D009944:Organoplatinum Compounds; D020097:Natriuretic Peptide, Brain; D019344:Lactic Acid; D002955:Leucovorin; D005472:Fluorouracil