Computed Tomographic Angiography Assessment of Epicardial Coronary Vasoreactivity for Early Detection of Doxorubicin-Induced Cardiotoxicity

BACKGROUND The vascular endothelium is a novel target for the detection, management, and prevention of doxorubicin (DOX)-induced cardiotoxicity. OBJECTIVES The study aimed to: 1) develop a methodology by computed tomography angiography (CTA) to evaluate stress-induced changes in epicardial coronary diameter; and 2) apply this to a chronic canine model of DOX-induced cardiotoxicity to assess vascular toxicity. METHODS To develop and validate quantitative methods, sequential retrospectively gated coronary CTAs were performed in 16 canines. Coronary diameters were measured at prespecified distances during rest, adenosine (ADE) (280 mg/kg/min), rest 30 min post-ADE, and dobutamine (DOB) (5 mu g/kg/min). A subgroup of 8 canines received weekly intravenous DOX (1 mg/kg) for 12 to 15 weeks, followed by rest-stress CTA at cumulative doses of similar to 4-mg/kg (3 to 5 mg/kg), similar to 8-mg/kg (7 to 9 mg/kg), and similar to 12-mg/kg (12 to 15 mg/kg) of DOX. Echocardiograms were performed at these timepoints to assess left ventricular ejection fraction and global longitudinal strain. RESULTS Under normal conditions, epicardial coronary arteries reproducibly dilated in response to ADE (left anterior descending coronary artery [LAD]: 12 +/- 2%, left circumflex coronary artery [LCx]: 13 +/- 2%, right coronary artery [RCA]: 14 +/- 2%) and DOB (LAD: 17 +/- 3%, LCx: 18 +/- 2%, RCA: 15 +/- 3%). With DOX, ADE vasodilator responses were impaired after similar to 4-mg/kg (LAD: -3 +/- 1%, LCx: 0 +/- 2%, RCA: -5 +/- 2%) and similar to 8-mg/kg (LAD: -3 +/- 1%, LCx: 0 +/- 1%, RCA: -2 +/- 2%). The DOB dilation response was preserved at similar to 4-mg/kg of DOX (LAD: 18 +/- 4%, LCx: 11 +/- 3%, RCA: 11 +/- 2%) but tended to decrease at similar to 8-mg/kg of DOX (LAD: 4 +/- 2%, LCx: 8 +/- 3%, RCA: 3 +/- 2%). A significant left ventricular ejection fraction reduction was observed only at 12 to 15 mg/kg DOX (baseline: 63 +/- 2%, 12-mg/kg: 45 +/- 3%). Global longitudinal strain was abnormal at similar to 4-mg/kg of DOX (p = 0.011). CONCLUSIONS CTA can reliably assess epicardial coronary diameter in response to pharmacological stressors, providing a noninvasive functional index of coronary vasoreactivity. Impaired epicardial vasodilation occurs early in DOX-induced cardiotoxicity. (C) 2020 Published by Elsevier on behalf of the American College of Cardiology Foundation.