CMR Diffusion Tensor Imaging Provides Novel Imaging Markers of Adverse Myocardial Remodeling in Aortic Stenosis

Objectives This study sought to determine microstructural cardiac remodeling in aortic stenosis (AS) and its reversibility following valve replacement using cardiovascular magnetic resonance (CMR) diffusion tensor imaging (DTI). Background Myocardial involvement in AS, such as focal and diffuse fibrosis is associated with worse outcome, even after timely aortic valve replacement (AVR). Alterations of myofiber architecture and myocardial diffusion may precede fibrosis, but its extent and reversibility after AVR are unknown. Methods Patients with isolated severe AS (n = 21, 62% male; mean age 75 years) and sex-matched senior control subjects underwent prospective CMR DTI. Changes in the DTI parameters: mean diffusivity (MD), fractional anisotropy (FA) as well as helix angle (HA) and absolute E2A sheet angle (E2A) were quantified and compared with native T1 and extracellular volume (ECV) as standard CMR markers of myocardial fibrosis. Six months after AVR eleven patients were scheduled for a follow-up CMR. Results In AS patients, significantly elevated MD (p = 0.002) and reduced FA (p< 0.001) were measured when compared to controls. Myocyte aggregate orientation exhibited a steeper transmural HA slope (p< 0.001) and increased absolute E2A sheet angle (p< 0.001) in AS. Six months post AVR, the HA slope (p< 0.001) was reduced to the level of healthy controls and MD (p = 0.014), FA (p = 0.011) and E2A (p = 0.003) showed a significant regression towards normal values. In contrast, native T1 was similar in AS and controls and did not change significantly after AVR. ECV showed a non-significant trend (p = 0.16) to higher values after AVR. Conclusion In patients with severe aortic stenosis, CMR DTI provides a set of parameters that identifies structural and diffusion abnormalities, which are largely reversible after AVR. DTI parameters showed proportionally greater changes in response to AS and AVR compared to metrics of myocardial fibrosis and may, therefore, aid risk stratification in earlier stages of severe AS. Condensed Abstract CMR diffusion tensor imaging (DTI) is a novel, noninvasive technique that allows for the assessment of myocardial microstructure in diseased hearts. We used CMR DTI to investigate myocardial involvement in patients with aortic stenosis (AS) before and after aortic valve replacement (AVR). Measures of tissue diffusion as well as parameters of myocyte orientation were significantly altered by AS and showed a clear trend towards normalization after AVR. Conventional markers of myocardial fibrosis (native T1 & extracellular volume) did not change significantly after AVR. Therefore, CMR DTI may unlock a new level of detail for phenotyping myocardial involvement in AS with potential value for improved risk stratification by visualizing earlier stages of adverse remodeling. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by grants from the Swiss National Science Foundation, Bern, Switzerland (CR23I3\_166485 & PZ00P2\_174144) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was approved by the ethics committee of the canton of Zurich (PB_2016-01944) and conformed to the principles of the Helsinki Declaration. Prior to imaging, written informed consent was obtained from all study subjects. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data availability is subject to reasonable request and ethical guidelines * AS : aortic stenosis AVR : aortic valve replacement BSA : body surface area bSSFP : balanced steady-state free precession CMR : cardiovascular magnetic resonance DCM : dilated cardiomyopathy DTI : diffusion tensor imaging E2A : absolute E2A sheet angle ECV : extracellular volume FA : fractional anisotropy GBCA : gadolinium based contrast agent HA : helix angle HCM : hypertrophic cardiomyopathy IVSd : interventricular septum thickness in diastole LGE : late gadolinium enhancement LV EDV : left ventricular end-diastolic volume LV EF : left ventricular ejection fraction LV Mi : left ventricular indexed mass MD : mean diffusivity MOLLI : modified look-locker inversion recovery RV EDV : right ventricular end-diastolic volume RV EF : right-ventricular ejection fraction