Weekly doxorubicin increases coronary arteriolar wall and adventitial thickness.

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). CONCLUSION: 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.

Novel approach to early detection of doxorubicin cardiotoxicity by gadolinium-enhanced cardiovascular magnetic resonance imaging in an experimental model.

BACKGROUND: We sought to determine whether cardiovascular magnetic resonance measures of gadolinium (Gd) signal intensity (SI) within the left ventricular myocardium are associated with future changes in left ventricular ejection fraction (LVEF) after receipt of doxorubicin (DOX). METHODS AND RESULTS: Forty Sprague-Dawley rats were divided into 3 groups scheduled to receive weekly intravenous doses of normal saline (n = 7), 1.5 mg/kg DOX (n = 19), or 2.5 mg/kg DOX (n = 14). Magnetic resonance determinations of LVEF and myocardial Gd-SI were performed before and at 2, 4, 7, and 10 weeks after DOX initiation. During treatment, animals were euthanized at different time points so that histopathologic assessments of the left ventricular myocardium could be obtained. Within-group analyses were performed to examine time-dependent relations between Gd-SI and primary events (deterioration in LVEF or an unanticipated death). Six of 19 animals receiving 1.5 mg/kg DOX and 10 of 14 animals receiving 2.5 mg/kg DOX experienced a primary event; no normal saline animals experienced a primary event. In animals with a primary event, histopathologic evidence of myocellular vacuolization occurred (P = 0.04), and the Gd-SI was elevated relative to baseline at the time of the event (P < 0.0001) and during the measurement period before the event (P = 0.0001). In all animals (including normal saline) without an event, measures of Gd-SI did not differ from baseline. CONCLUSIONS: After DOX, low serial measures of Gd-SI predict an absence of an LVEF drop or unanticipated death. An increase in Gd-SI after DOX forecasts a subsequent drop in LVEF as well as histopathologic evidence of intracellular vacuolization consistent with DOX cardiotoxicity.