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

Figures

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  Figure 1. Study Timeline A group of canines (n = 8) were administered doxorubicin (DOX) (1 mg/kg) weekly for 12–15 weeks. (A) Serial contrast coronary computed tomography angiography (CTA) was performed at baseline, and after ∼4-mg/kg and ∼8-mg/kg cumulative dose of doxorubicin (DOX), as indicated by the red arrows. Transthoracic echocardiography (TTE) was performed at baseline, and after ∼4-, ∼8- and ∼12-mg/kg cumulative DOX doses, as indicated by the blue arrows. (B) The sequence of each rest and pharmacological stress CTA imaging session. (C) Representative multiplanar reformatted CTA images acquired at REST-1 and after administration of adenosine (ADE).

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  Figure 2. Plots of Correlation and Agreement Between REST-1 and REST-2 Diameters (A) Correlation between REST-1 and REST-2 coronary diameters, including all baseline analyzed coronary segments (n = 48 pairs). Please note that in case of identical diameter values, the data points may overlap. (B) Bland-Altman plot analysis including all baseline REST-1 and REST-2 coronary diameters (n = 48 pairs). The solid line represents zero, the central dashed line indicates bias, and the 2 outer dashed lines indicate the 95% limits of agreement. CI = confidence interval; ICC = intraclass correlation coefficient.

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  Figure 3. Hemodynamic Analysis Change in (A) mean arterial pressure (MAP) and (B) heart rate (HR) compared with resting values in response to adenosine (ADE) and dobutamine (DOB). The boxes represent the 25th to 75th percentiles, the midlines represent the median values, and the whiskers indicate minimal and maximal values, n = 8 for each group.

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  Figure 4. Serial Echocardiographic Analysis (A) End-diastolic volume (EDV) and end-systolic volume (ESV), (B) intraventricular septum diameter (IVSd) and left ventricular posterior wall diameter (LVPWd), (C) end-diastolic left ventricular internal diameter (LVIDd), (D) left ventricular ejection fraction (EF), and (E) global longitudinal strain (GLS) were assessed by transthoracic echocardiography in canines undergoing doxorubicin (DOX) therapy (n = 8). Asterisks indicate significant change compared with baseline measurements.

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  Figure 5. Histology Assessment of Myocardial Biopsy and Autopsy Specimens (Top) Representative hematoxylin and eosin photomicrographs in a canine model of chronic DOX cardiotoxicity show the average severity of myocardial injury increases with dose over time within the left ventricle. Biopsies collected at ∼4 mg/kg and ∼8 mg/kg and the terminal time point show scattered shrunken (gray arrowhead) and hypertrophied (black arrows) tissue at each time point; however, cardiomyocyte vacuolation (gray arrows) and hypereosinophilic cytoplasm (black arrows) are common at the terminal necropsy time point. (Bottom) Myocardial toxicity severity score in biopsy specimens and terminal autopsy samples with different cumulative doses of doxorubicin.

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  Figure 6. Rest-Stress Computed Tomography Angiography Analysis Coronary diameters (n = 8 in each group) in the left anterior descending coronary artery (LAD), left circumflex coronary artery (LCx), and right coronary artery (RCA) at baseline and after ∼4 mg/kg and ∼8 mg/kg of cumulative intravenous doxorubicin (DOX) treatment. Coronary diameters were assessed at rest (REST-1), in response to adenosine (ADE), at rest 30 min after discontinuation of ADE (REST-2), and during dobutamine (DOB) infusion.

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  Central Illustration. Impaired Vasoreactivity in DOX-Induced Cardiotoxicity This study used a novel computed tomography (CT) methodology to demonstrate impaired adenosine (ADE)- and dobutamine (DOB)-induced coronary vasoreactivity in a large animal model of chronic doxorubicin (DOX)-induced cardiotoxicity. Left ventricular ejection fraction (LVEF) was not reduced until a cumulative DOX dose of 12 to 15 mg/kg was administered. Impairment in ADE-induced vasodilator responses occurred early in the progression of DOX-induced cardiotoxicity similar to impairment in global longitudinal strain (GLS). 2D = 2-dimensional; TTE = transthoracic echocardiography.

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  Figure 7. Schematic Representation of ADE and DOB-Induced Epicardial Vasodilation Blue coloring indicates primarily endothelial-mediated processes, green coloring primarily smooth muscle–mediated processes, and brown coloring primarily cardiomyocyte-mediated processes. A2 = adenosine receptor 2; ADE = adenosine; DOB = dobutamine; DOX = doxorubicin; eNOS = endothelial nitric oxide synthase; Gq = G protein q; Gs = G protein s; NO = nitric oxide; SMC = smooth muscle cell.