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Published on: October 14, 2016
Computed Tomographic Angiography Assessment of Epicardial Coronary Vasoreactivity for Early Detection of
Attila Feher1,2, Nabil E Boutagy1,2, John C Stendahl1,2
1Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
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.
Insights
Computed tomography angiography (CTA) can detect early vascular changes in doxorubicin (DOX)-induced cardiotoxicity by assessing epicardial coronary vasoreactivity. This noninvasive method reveals impaired vasodilation before significant heart function decline.
Area of Science:
- Cardiovascular Research
- Medical Imaging
- Pharmacology
Background:
- The vascular endothelium is a key target for understanding and managing doxorubicin (DOX)-induced cardiotoxicity.
- Early detection of DOX cardiotoxicity is crucial for patient management and prevention strategies.
Purpose of the Study:
- To develop and validate computed tomography angiography (CTA) methods for evaluating stress-induced changes in epicardial coronary artery diameter.
- To apply CTA to a canine model of DOX-induced cardiotoxicity to assess vascular toxicity.
Main Methods:
- Quantitative coronary CT angiography (CTA) was performed in canines at rest and during pharmacological stress (adenosine and dobutamine).
- A subgroup of canines received chronic doxorubicin (DOX) treatment, with serial CTA and echocardiography to assess vascular and cardiac function.
- Epicardial coronary diameters were measured to evaluate vasoreactivity changes following DOX administration.
Main Results:
- Pharmacological stressors (adenosine, dobutamine) reliably induced epicardial coronary artery dilation in healthy canines.
- Doxorubicin (DOX) treatment led to impaired adenosine-mediated vasodilation early in the toxicity course (around 4-8 mg/kg cumulative dose).
- Left ventricular ejection fraction reduction was significant only at higher DOX doses (12-15 mg/kg), while global longitudinal strain was affected earlier.
Conclusions:
- CTA provides a reliable, noninvasive method to assess functional epicardial coronary vasoreactivity using pharmacological stressors.
- Impaired epicardial vasodilation is an early indicator of DOX-induced cardiotoxicity, detectable before substantial changes in cardiac function.
- CTA offers a promising tool for early detection and monitoring of vascular toxicity in patients receiving doxorubicin.
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