Towards a precision medicine approach to the management of aortic stenosis

BackgroundDefinitive treatments for severe symptomatic aortic stenosis (AS) include surgical aortic valve replacement and transcatheter aortic valve implantation. However, the optimal timing for valve intervention in asymptomatic severe AS remains debated and sociodemographic disparities in the treatment of AS have been reported. Cardiac magnetic resonance (CMR) imaging provides advanced biomarkers to improve risk stratification.Aims(i) Understand sociodemographic differences in the referral for and treatment of AS in England, (ii) establish the prognostic role of myocardial perfusion reserve (MPR) or coronary flow reserve (CFR) in AS and assess the impact of AVR on CMR-measured imaging biomarkers, including MPR and myocardial calcium handling and (iii) to compare the impact of early AVR vs standard care on the overall myocardial fibrosis burden and reverse remodelling in randomised cohort of patients with asymptomatic severe AS.Methods (i) Real-world data from a national database were used to determine sociodemographic characteristics, referral patterns and intervention rates for AS. (ii) A systematic review/metaanalysis assessed the prognostic significance of MPR/CFR. (iii) CMR studies evaluated the effect of intervention on cardiac remodeling, MPR, aerobic capacity, calcium handling and myocardial fibrosis.Results(i) Of 154,223 patients (50.4% female) with AS, 92.7% were White, 2.7% South Asian, 1.4% Black and 1.1% Other/Mixed. Women and deprived socioeconomic groups had lower referral to secondary care and intervention rates, while ethnic minorities had higher referral but lowerint ervention rates. (ii) Impaired MPR/CFR was associated with a higher incidence of MACE (HR 3.67, 95% CI: 1.66, 8.09, I2 = 63%) in 384 participants with 109 events. (iii) In a pooled analysis (n=50), MPR improved significantly 6-12 months post-AVR, with greater improvements in those with impaired baseline perfusion and correlating with improvement in aerobic exercise capacity. In a pilot manganese enhanced CMR study (n=7), no notable change in calcium handling was seen post AVR. Interim results from 83 asymptomatic patients with severe AS, randomised to early intervention vs standard care, showed greater preservation of LV systolic function in the early intervention group. Signals of less fibrosis accumulation with early intervention, did not remain significant on adjusted analysis.ConclusionsThis thesis identified sociodemographic disparities in AS management in England. It demonstrated the utility of advanced imaging biomarkers, especially the prognostic role of MPR in AS. Intervention improves MPR, however it does not alter myocardial calcium handling. Early intervention shows promise for preservation of systolic function and signals of less fibrosis accumulation, but data analysis of the full cohort (currently under follow-up) are needed.