Quantification of myocardial interstitial fibrosis and extracellular volume for the detection of cardiac allograft vasculopathy
In search of a non-invasive alternative detection of early-stage cardiac allograft vasculopathy (CAV), in this preliminary study we tested the hypothesis that interstitial fibrosis quantified with cardiac magnetic resonance (CMR) can serve as a biomarker for the detection of CAV. Late-stage CAV was detected with routine X-ray coronary angiography (XRCA), while a coronary intima-media thickness ratio (IMTR) > 1 on optical coherence tomography (OCT) was used to detect early-stage CAV. Interstitial fibrosis was quantified in the endomyocardial biopsy (EMB) and indirectly with CMR as the T1 relaxation time and extracellular volume (ECV). CMR was performed within 48 h of a single invasive procedure with XRCA, OCT, and EMB procurement in stable HTx recipients (n = 27; age 54 ± 13 years, 5.4 ± 3.7 years post-transplant). XRCA-CAV and IMTR > 1 were present in 15% and 75% of study patients, respectively. The T1 relaxation times and ECV were increased in patients with XRCA-CAV (p = 0.03 each), while IMTR and EMB interstitial fibrosis were not significantly different (both p > 0.05). ECV (ρ = 0.46, p = 0.02) and IMTR (ρ = 0.58; p = 0.01) correlated with the histological quantity of interstitial fibrosis, while the T1 relaxation time (p = 0.06) did not. The correlation of the IMTR with the EMB interstitial fibrosis tentatively validates the hypothesis that interstitial fibrosis may serve as an early indicator of CAV. Moreover, the significant association of CMR-based ECV with the magnitude of interstitial fibrosis in the biopsy suggests ECV as a potential biomarker for interstitial fibrosis due to early-stage CAV. The measurement of ECV may therefore have a role for non-invasive detection and follow-up of early-stage CAV.
KeywordsCardiac allograft vasculopathy Interstitial fibrosis Cardiovascular magnetic resonance Extracellular volume Optical coherence tomography Heart transplantation
This work was supported by grants from the Swiss Heart Foundation to RH, JAMB and RBvH, and from the Swiss National Science Foundation to RBvH (PZ00P3_154719 and 32003B_182615), RH (320030_147121), JAMB (PZ00P3_167871) and MS (320030_143923, 326030_150828, and 320030_173129). MS received non-monetary research support from Siemens Healthineers.
RBvH, JAMB, JY, and GG acquired, analysed and interpreted the CMR data. JFI and SD acquired, analysed and interpreted the OCT and X-ray data. SR and JLB performed and analysed the histology and interpreted its results. MK and PT performed the transplantation surgery. MK, JR, NL, and PT recruited subjects and collected clinical data. RBvH, MS, and RH designed the study and integrated the various results. RBvH and RH drafted the initial manuscript. All authors read and approved the final manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Cantonal Ethics Committee for Research in the Canton of Vaud—CER-VD, Protocol 2016-00635) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individual participants included in the study.
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