Impact of time-of-the-day of aortic valve replacement on peri-operative inflammation and subsequent cardiac reverse remodeling. – TOMIS-leukocyte

Background. Aortic valve replacement is the sole therapeutic solution to improve outcomes in patients with aortic stenosis. AVR is commonly performed during on-pump cardiac surgery, whereas trans-catheter aortic valve implantation is increasingly performed in patients with high-risk for surgery complications. Whatever the technical approach, AVR is expected to improve not only survival, but also functional status as a result of cardiac reverse remodeling, i.e. regression of the left ventricular hypertrophy. No medication is currently available to specifically improve and/or accelerate reverse remodeling after AVR.
We have recently demonstrated that afternoon (vs. morning) AVR results in decreased incidence of both immediate perioperative myocardial infarction and acute heart failure within 500 days after surgery. Interestingly, disruption of diurnal rhythms by modulating molecular clock genes immediately after myocardial infarction in mice impaired healing and exacerbated maladaptive cardiac remodeling.
Working hypothesis. We postulate that the circadian clock plays a key role in immune cell recruitment and peri-operative myocardial injury healing and remodeling after AVR, i.e. differences in pre- and post-operative immune-inflammatory responses and subsequent cardiac repair and remodeling are responsible for the lower frequency of heart failure development months after afternoon (vs. morning) AVR.
Objectives and methods. The project will be organized to determine: (i) the impact of peri-operative inflammation on surgery complications and subsequent cardiac remodeling after AVR, (ii) the impact of the time-of-day on peri-operative inflammatory responses and their role in post-operative outcomes.
We will perform a bi-centric prospective randomized study at the University Hospital CHU de Lille (France) and CHU Rennes (France) in patients undergoing first AVR for severe aortic stenosis with LVEF>50% to determine whether the pre-operative leukocyte immune-phenotype and their post-operative activation display a morning-afternoon variation, and whether this activation is associated with reverse cardiac remodeling during the year following AVR. Deep immuno-phenotyping of peripheral blood leukocytes will be performed by mass cytometry (CYTOF). Second, the transcriptional pathways associated with the time-of-the-day variation and AVR-induced immune-phenotype will be explored in cells identified in previous WP by RNAseq analysis. Third, based on our previous studies, we will determine the role of the clock gene REV-ERB? in the regulation of the time-of-the-day variation of the immune-inflammatory response and its impact on cardiac remodeling. We will perform functional analysis on freshly isolated human monocyte sub-populations and study cardiac remodeling after abdominal aortic constriction (AAC) and reverse remodelling after AAC relief in mouse models deficient for REV-ERB? (cell type to be chosen based on the results from other WP). Finally, studies using novel REV-ERB? ligands will be done to validate this target as a pharmacological approach.
Expected results and relevance of the project. Our translational project including patients and preclinical models will identify the contribution of the immune-inflammatory response in maladaptive cardiac healing and reverse remodeling after AVR., as well as proof-of-concept studies for feasible therapeutic strategies interfering with clock gene signaling in immune-inflammatory cells to prevent maladaptive cardiac remodeling for which virtually no drugs exist to date.