title: Weekly doxorubicin increases coronary arteriolar wall and adventitial thickness.
abstract: BACKGROUND
  Doxorubicin (DOX) is associated with premature cardiovascular events including myocardial infarction. This study was performed to determine if the weekly administration of DOX influenced coronary arteriolar medial and/or adventitial wall thickening.
  
  
  METHODS
  Thirty-two male Sprague-Dawley rats aged 25.1± 2.4 weeks were randomly divided into three groups and received weekly intraperitoneal injections of normal saline (saline, n = 7), or low (1.5 mg/kg to 1.75 mg/kg, n = 14) or high (2.5 mg/kg, n = 11) doses of DOX. The animals were treated for 2-12 weeks, and euthanized at pre-specified intervals (2, 4, 7, or 10+ weeks) to obtain histopathologic assessments of coronary arteriolar lumen diameter, medial wall thickness, adventitial wall thickness, and total wall thickness (medial thickness + adventitial thickness).
  
  
  RESULTS
  Lumen diameter was similar across all groups (saline: 315±34 µm, low DOX: 286±24 µm, high DOX: 242±27 µm; p = 0.22). In comparison to animals receiving weekly saline, animals receiving weekly injections of 2.5 mg/kg of DOX experienced an increase in medial (23±2 µm vs. 13±3 µm; p = 0.005), and total wall thickness (51±4 µm vs. 36±5 µm; p = 0.022), respectively. These increases, as well as adventitial thickening became more prominent after normalizing for lumen diameter (p<0.05 to p<0.001) and after adjusting for age, weight, and total cumulative DOX dose (p = 0.02 to p = 0.01). Animals receiving low dose DOX trended toward increases in adventitial and total wall thickness after normalization to lumen diameter and accounting for age, weight, and total cumulative DOX dose (p = 0.06 and 0.09, respectively).
  
  
  CONCLUSIONS
  In conclusion, these data demonstrate that weekly treatment of rats with higher doses of DOX increases coronary arteriolar medial, adventitial, and total wall thickness. Future studies are warranted to determine if DOX related coronary arteriolar effects are reversible or preventable, exacerbate the known cardiomyopathic effects of DOX, influence altered resting or stress-induced myocardial perfusion, or contribute to the occurrence of myocardial infarction.
authors: Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America.
authors: Delrae M
authors: DM
authors: Eckman
authors: R Brandon
authors: RB
authors: Stacey
authors: Robert
authors: R
authors: Rowe
authors: Ralph
authors: R
authors: D'Agostino
authors: Nancy D
authors: ND
authors: Kock
authors: David C
authors: DC
authors: Sane
authors: Frank M
authors: FM
authors: Torti
authors: Joseph
authors: J
authors: Yeboah
authors: Susan
authors: S
authors: Workman
authors: Kimberly S
authors: KS
authors: Lane
authors: W Gregory
authors: WG
authors: Hundley
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D059168:Carotid Intima-Media Thickness; D003331:Coronary Vessels / Q000187:drug effects*; D004317:Doxorubicin / Q000009:adverse effects*; D004334:Drug Administration Schedule; D007274:Injections, Intraperitoneal; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin