Author + information
- Attila Feher, MD, PhDa,b,∗,
- Nabil E. Boutagy, PhDa,b,∗,
- John C. Stendahl, MD, PhDa,b,
- Christi Hawleyb,
- Nicole Guerrera, RDCSb,
- Carmen J. Booth, DVM, PhDc,
- Eva Romito, PhDa,b,
- Steven Wilson, VMDc,
- Chi Liu, PhDd and
- Albert J. Sinusas, MDa,b,d,e,∗ (, )@attilafehermd
- aSection of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
- bYale Translational Research Imaging Center, Yale University, New Haven, Connecticut
- cDepartment of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut
- dDepartment of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut
- eDepartment of Biomedical Engineering, Yale University School of Medicine, New Haven, Connecticut
- ↵∗Address for correspondence:
Dr. Albert J. Sinusas, Section of Cardiovascular Medicine, Yale University School of Medicine, P.O. Box 208017, Dana 3, New Haven, Connecticut 06520-8017.
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 μg/kg/min), rest 30 min post-ADE, and dobutamine (DOB) (5 μg/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 ∼4-mg/kg (3 to 5 mg/kg), ∼8-mg/kg (7 to 9 mg/kg), and ∼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 ∼4-mg/kg (LAD: –3 ± 1%, LCx: 0 ± 2%, RCA: –5 ± 2%) and ∼8-mg/kg (LAD: –3 ± 1%, LCx: 0 ± 1%, RCA: –2 ± 2%). The DOB dilation response was preserved at ∼4-mg/kg of DOX (LAD: 18 ± 4%, LCx: 11 ± 3%, RCA: 11 ± 2%) but tended to decrease at ∼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 ∼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.
↵∗ Drs. Feher and Boutagy contributed equally to this work.
This work was supported by the National Institute of Health grants HL123949 (to Dr. Liu), HL098069 (to Dr. Sinusas), and S10RR025555 (to Dr. Sinusas). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: CardioOncology author instructions page.
- Received March 15, 2020.
- Revision received May 8, 2020.
- Accepted May 11, 2020.