Cardiac MRI: a Translational Imaging Tool for Characterizing Anthracycline-Induced Myocardial Remodeling

Abstract

Cardiovascular side effects of cancer therapeutics are the leading causes of morbidity and mortality in cancer survivors. Anthracyclines (AC) serve as the backbone of many anti-cancer treatment strategies, but dose-dependent myocardial injury limits their use. Cumulative AC exposure can disrupt the dynamic equilibrium of the myocardial microarchitecture while repeated injury and repair leads to myocyte loss, interstitial myocardial fibrosis, and impaired contractility. Although children are assumed to have greater myocardial plasticity, AC exposure at a younger age portends worse prognosis. In older patients, there is lower overall survival once they develop cardiovascular disease. Because aberrations in the myocardial architecture predispose the heart to a decline in function, early detection with sensitive imaging tools is crucial and the implications for resource utilization are substantial. As a comprehensive imaging modality, cardiac magnetic resonance (CMR) imaging is able to go beyond quantification of ejection fraction and myocardial deformation to characterize adaptive microstructural and microvascular changes that are important to myocardial tissue health. Herein, we describe CMR as an established translational imaging tool that can be used clinically to characterize AC-associated myocardial remodeling.

Keywords: Anthracyclines; Cardiac magnetic resonance imaging; Cardio-oncology; Cardiotoxicity; Translational imaging.

Figure 1

Anthracycline-associated myocyte damage (A-D) and extracellular matrix remodeling (1–4). Topoisomerase 2B is the primary mediator of AC-induced cardiotoxicity and causes direct ds-DNA breakage, impaired mitochondrial biogenesis, and ROS production. AC passively diffuses into the myocyte to trigger signaling pathways of myocardial injury and repair. (A) Iron-anthracycline complexes cause ROS generation, which leads to lipid peroxidation and membrane damage. (B) In the mitochondrion, DOX-induced ROS causes release of cytochrome C leading to cell death. (C) AC binds to proteasomes with high affinity and translocate into the nucleus to intercalate into DNA. As DNA damage increases, apoptosis pathways are activated. (D) Increased cellular stress by ROS generation leads to increased MMP expression. Compensatory ECM remodeling is reflected as (1) actin cytoskeleton activity at the cell-ECM interface, (2) MMP-induced collagen breakdown and turnover which can lead to fibrosis (scar) formation, 3) myofibroblast proliferation to increase matrix protein (fibronectin) deposition secondary to SDC-1 shedding, and (4) cystatin C /cathepsin mediated fibronectin turnover. AC, anthracycline; ds, double-stranded; ECM, extracellular matrix; MMP, matrix metalloproteinase; ROS, reactive oxygen species; SDC-1, syndecan-1; Top 2β, topoisomerase 2 β. Adapted and reproduced with permission (Chest. 2014; 146(4):1123–1130).

Figure 2

Comprehensive CMR imaging (1.5 Tesla) of a 33-year old male with anthracycline exposure at age 12. (A) Morphologic myocardial characterization using cardiac cine imaging (end-diastole) demonstrates reduced left ventricular mass (myocyte loss), ventricular dilation, increased ventricular trabeculation, but normal left ventricular and right ventricular ejection fraction. (B) Myocardial tagging can be performed using conventional Cartesian grid tags (left) or radial polar tags (right). (C) Late gadolinium enhancement imaging demonstrates no regional fibrosis. (D) Pre-contrast T1 map (left, average T1 970 ms) and post-contrast (right, average T1 471 ms) using MOLLI were performed. (E) ECV maps using MOLLI (left, ECV 0.22±0.02) and InSiL (right, ECV 0.22±0.03) demonstrate no diffuse fibrosis. InSiL [100] is a modified T1 mapping algorithm that allows for improved estimation of T1 time with less heart rate dependence. ECV reference range 0.23–0.32 (based on MOLLI). ECV, extracellular volume fraction; InSiL, instantaneous signal loss simulation; MOLLI, modified Look-Locker inversion recovery; bSSFP, balanced steady state free precession.