Abstract
BackgroundDoxorubicin (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.MethodsThirty-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).ResultsLumen 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±2µm vs. 13±3µm; p = 0.005), and total wall thickness (51±4µm vs. 36±5µm; 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).ConclusionIn 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.
Highlights
Cardiovascular (CV) events including myocardial infarction (MI), stroke, and congestive heart failure (CHF) are the second leading cause of premature morbidity and mortality for those surviving beyond 5 years of their initial diagnosis for breast cancer or a hematologic malignancy such as Hodgkin’s disease or NonHodgkin’s lymphoma [1,2,3]
A commonality among treatment for these cancers is the administration of anthracycline chemotherapy with agents such as doxorubicin (DOX)
We investigated the association between the administration of DOX and histopathologic changes in coronary arteriolar microcirculatory arterial segments
Summary
Cardiovascular (CV) events including myocardial infarction (MI), stroke, and congestive heart failure (CHF) are the second leading cause of premature morbidity and mortality for those surviving beyond 5 years of their initial diagnosis for breast cancer or a hematologic malignancy such as Hodgkin’s disease or NonHodgkin’s lymphoma [1,2,3]. There are relatively few studies that have focused on understanding potential mechanisms by which patients exposed to DOX or other anthracyclines might experience altered myocardial blood flow or sustain a MI. To this end, we investigated the association between the administration of DOX and histopathologic changes in coronary arteriolar microcirculatory arterial segments. We evaluated 2 doses of DOX in a rat model without coronary arterial atherosclerosis These doses were selected to mimic doses commonly administered to patients receiving DOX for treatment of breast cancer or lymphoma. This study was performed to determine if the weekly administration of DOX influenced coronary arteriolar medial and/or adventitial wall thickening
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