br cellular metabolism in response to anthracycline

cellular metabolism in response to anthracycline therapy, which is affecting only a subset of all patients [5]. Personalised approaches to rec-ognition of early myocardial changes during the course of cancer thera-pies may help to detect and prevent the late consequences of cardiac involvement by guiding early prevention [6,7]. Studies reported globally reduced left ventricular (LV) ejection fraction (LV-EF), mainly on the ac-count of enlarged end-systolic volume (LV-ESV). Additionally, reduced longitudinal deformation, impaired diastolic function and rise of sero-logical cardiac biomarkers, including troponin and NT-proBNP have been reported [5–9]. Retrospective patient studies reported signifi-cantly elevated myocardial T1 mapping indices, sensitive and direct measures of diffusely abnormal myocardial involvement by cardiac magnetic resonance (CMR) [8–11]. These findings were corroborated in an experimental study with T1 and T2 mapping, further highlighting the role of early inflammatory involvement followed by diffuse fibrotic remodelling [12]. In this study, we investigated patients receiving cancer-related treatments within the first 3 months (early Tx) or N12 months prior (late Tx) for the phenotypical evidence of myocardial injury using CMR. We compared the findings, firstly to age-gender and CV risk factors matched controls, and secondly, to observations in an in-dependent cohort of similar patients with longitudinal assessments.
2. Methods
One hundred and fifteen patients (≥18 years) without previously known or symptom-atic cardiac disease were referred for screening of cardiac involvement due to cancer-related treatment from local oncology departments (London, n = 82, Frankfurt, n = 33, the original cohort). Non-exposed subjects, matched for age, gender and CV risk factor pro-file, with low pretest likelihood for cardiomyopathy or previous history of cardiac events or coronary artery disease, with no clinical or serological evidence for systemic inflamma-tion, taking no anti-inflammatory medication, served as controls (n = 57). An indepen-dent cohort of patients underwent longitudinal assessments at 2, 12 and 18 months after receipt of treatment (n = 25, Frankfurt, the longitudinal cohort). The general contra-indication to contrast-enhanced CMR were observed, including known allergy to gadolin-ium Chloramphenicol agents, pregnancy, cochlear implants, cerebral aneurysm clips and non-CMR compatible pacemakers (no subject was excluded due to these contraindications in the present study). Clinical meta-data was recorded for all patients (Table 1). The study pro-tocol was reviewed and approved by respective local ethics committees and written in-formed consent was obtained from all participants. All procedures were carried out in accordance with the Declaration of Helsinki. r> 2.1. Study procedures
All subjects underwent a standardised CMR protocol for routine assessment of cardiac volumes, mass, T1 and T2 mapping, myocardial perfusion and late gadolinium enhance-ment (LGE) [13,14], using 3-Tesla (T) scanners (Achieva, Philips Healthcare, Best, The Netherlands, and Skyra, Siemens Healthineers, Erlangen). In the longitudinal cohort, the serial follow-up assessments consisted of native T1 and T2 mapping and cardiac volumes only. Patients with symptoms and signs of systemic infection were not included. After standardised specific planning, volumetric cavity assessment was performed by whole-heart coverage of short-axis (SAX) slices. Myocardial mapping acquisitions were made in a single midventricular SAX slice using the investigator-specific modified Look-Locker Imaging (FFM-MOLLI) [15,16] for T1 mapping. A hybrid gradient and spin echo (GraSE) se-quence [17,18] at the London site and T2-FLASH sequence [19,20] at the Frankfurt site for T2 mapping. All sequence types and parameters have been validated and published previ-ously. Sequence-specific normal ranges were employed (FFM MOLLI native T1: 3.0-T: mean of the normal range 1052 ± 23 ms; i.e. upper limit of normal range: 1098 ms at 3.0-T) [21], native T2: GraSE sequence: 45 ± 4 ms [17], T2-FLASH sequence 35 ± 4 ms [19,22]. Myocardial perfusion imaging with adenosine infusion (140–210 μg/kg/min) with dynamic acquisition during administration of 0.1 mmol/kg body weight gadobutrol (Gadovist®, Bayer AG, Leverkusen, Germany) [23]. LGE was performed in a SAX stack ~15 min after contrast agent administration, using a mid-diastolic inversion prepared 2-dimensional gradient echo sequence (TE/TR/flip-angle 2.0 ms/3.4 ms/25°, acquired voxel size 1.4 × 1.4 × 8 mm) with individually adapted prepulse delay to achieve optimally nulled myocardium.