Author + information
- Published online March 13, 2019.
- Mimount Bourfiss, MD,
- Niek H.J. Prakken, MD, PhD,
- Jeroen F. van der Heijden, MD, PhD,
- Ihab Kamel, MD, PhD,
- Stefan L. Zimmerman, MD,
- Folkert W. Asselbergs, MD, PhD,
- Tim Leiner, MD, PhD,
- Birgitta K. Velthuis, MD, PhD and
- Anneline S.J.M. te Riele, MD, PhD∗ ()
- ↵∗Division of Cardiology, Department of Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
Correct identification of arrhythmogenic right ventricular cardiomyopathy (ARVC) is pertinent because ventricular arrhythmias can occur early in the disease (1). Ventricular arrhythmias in ARVC typically have a re-entrant mechanism caused by diffuse fibrosis. Although late gadolinium enhancement (LGE) cardiac magnetic resonance cannot quantitatively assess diffuse changes (2), native T1 mapping is a promising technique to detect diffuse fibrosis. In this proof-of-concept study, we aimed to analyze the value of native T1 mapping in ARVC.
We included subjects who underwent cardiac magnetic resonance (1.5-T, Achieva, Philips Medical Systems, Best, the Netherlands) with T1 mapping (Philips’ modification of the 5(3)3 Modified Look-Locker Imaging [MOLLI] sequence) (2). Included subjects (n = 43) were divided into 3 groups: 1) genotype-positive patients with ARVC as per 2010 diagnostic task force criteria (n = 13); 2) genotype-positive at-risk relatives not fulfilling task force criteria (n = 17); and 3) control subjects who were evaluated for ARVC but were eventually diagnosed with right ventricular outflow tract ventricular tachycardia (n = 13). Native T1 mapping was measured in the short-axis view according to the American Heart Association 16-segment model using cvi42 (Circle Cardiovascular Imaging version 5.6.6, Calgary, Canada). Global T1 values were calculated as mean native T1 times of all segments. T1 dispersion was calculated as the SD of native T1 times in all segments within a given patient. Intraobserver and interobserver variability were evaluated by remeasuring T1 times in 15 randomly selected subjects. We analyzed only left ventricular (LV) T1 mapping results because the thin right ventricular wall rendered T1 mapping susceptible to partial volume effects (overt patients [1,460 ± 211 ms] vs. relatives [1,336 ± 131 ms] vs. control subjects [1,360 ± 116 ms]).
Mean age was 37 ± 17 years, and 51% of the patients were female. There were no differences in age (p = 0.10) or sex (p = 0.53) between the groups. By design, all patients with overt ARVC and at-risk relatives carried a pathogenic mutation (plakophilin-2 [70%], phospholamban [27%], or desmoplakin [3%]). LV LGE was seen in 9 of 13 (69%) overt patients, in 7 of 17 (41%) relatives, and in no control subjects.
Mean LV T1 times were significantly higher in overt patients (1,067 ± 41 ms) compared with control subjects (1,038 ± 27 ms; p = 0.04), but no statistically significant difference was noted between relatives (1,055 ± 38 ms) and control subjects (p = 0.17). Additionally, T1 dispersion was significantly greater in both overt patients (93 ± 33 ms; p = 0.02) and relatives (79 ± 15 ms; p = 0.03) compared with control subjects (67 ± 12 ms). This was driven by elevated T1 times in the LV posterolateral (p ≤ 0.02) and inferior (p = 0.01) regions for both overt patients and relatives and in the anterior (p = 0.01) region for overt patients (Figures 1A to 1C). Using receiver-operating characteristic analysis (overt vs. control), the optimal threshold for abnormal T1 dispersion was >73 ms (sensitivity, 73%; specificity, 77%; area under the curve: 0.80). Interestingly, 11 of 17 (65%) at-risk relatives had abnormal T1 dispersion, and 64% (n = 7 of 11) of this group had no LGE or other signs of structural or electrical disease. The intraobserver and interobserver correlation of mean native T1 times was excellent (intraclass correlation coefficient ≥0.94).
This study is the first to compare T1 mapping between patients with ARVC and control subjects. Mean native T1 time was significantly higher in overt patients compared with control subjects, thus suggesting that the changes in cardiac microstructure are dominated by fibrosis rather than fatty replacement (decreases native T1 time). In addition, both genotype-positive patients with ARVC and at-risk relatives have a greater dispersion of native T1 times compared with control subjects, a finding that predominantly reflected changes in posterolateral and inferior regions. A previous study in patients with ARVC with a desmosomal or phospholamban mutation already showed that regional LV changes typically affect the posterolateral wall (3). Our results confirm and extend these findings by revealing that these changes can already be observed in asymptomatic mutation carriers before the development of an overt clinical phenotype. Moreover, a large proportion of at-risk relatives with elevated T1 dispersion had no LGE, a finding suggesting greater sensitivity for subtle ventricular changes.
We believe that the findings of this study may fuel future studies in a hypothesis-generating manner. Because our results were obtained in a small group of patients, these findings require larger prospective studies to determine the incremental diagnostic and prognostic value of T1 mapping over established tests for ARVC. Before clinical application, interstudy variability testing including assessment of post-processing methods and determination of reference values for native T1 times and dispersion will be essential. We did not evaluate extracellular volume because reliable hematocrit data were unavailable in most patients. Future studies should preferably include this measure in an evaluation of ARVC.
In conclusion, native T1 mapping helps differentiate patients with overt ARVC and at-risk relatives from control subjects, and it may have the potential to detect early ARVC.
Please note: This work has received funding from the Netherlands Cardiovascular Research Initiative, an initiative supported by the Dutch Heart Foundation (CVON2015-12 eDETECT and 2012-10 PREDICT). This project has received support from the European Union’s Horizon 2020 research and innovation program under the ERA-NET Co-fund action no. 680969 (ERA-CVD DETECTIN-HF), jointly funded by the Dutch Heart Foundation (2016T096) and the Netherlands Organization for Health Research and Development (ZonMw). The Netherlands ACM Registry (www.acmregistry.nl) is supported by the Netherlands Heart Institute (project 06901). Dr. Bourfiss has reported support from by the Alexandre Suerman Stipend of the University Medical Center (UMC) Utrecht. Dr. Te Riele has reported support from the Dutch Heart Foundation (grant no. 2015T058), the UMC Utrecht Fellowship Clinical Research Talent, and the CVON PREDICT Young Talent Program. Dr. Asselbergs has reported support from University College London Hospitals National Institute for Health Research Biomedical Research Center. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2019 American College of Cardiology Foundation
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