A Mendelian randomization analysis of cardiac MRI measurements as surrogate outcomes for heart failure and atrial fibrillation

Abstract

BACKGROUND: Drug development and disease prevention of heart failure (HF) and atrial fibrillation (AF) are impeded by a lack of robust early-stage surrogates. We determined to what extent cardiac magnetic resonance (CMR) measurements act as surrogates for the development of HF or AF. METHODS: Genetic data were sourced on the association with 21 atrial and ventricular CMR measurements. Mendelian randomization was used to determine CMR associations with AF, HF, non-ischaemic cardiomyopathy (NICM), and dilated cardiomyopathy (DCM), noting that the definition of NICM includes DCM as a subset. Additionally, for the CMR surrogates of AF and HF, we explored their association with non-cardiac traits potentially influenced by cardiac disease liability. RESULTS: In total we find that 7 CMR measures (biventricular ejection fraction (EF) and end-systolic volume (ESV), as well as LV systolic volume (SV), end-diastolic volume (EDV), and mass to volume ratio (MVR)) associate with the development of HF, 5 with the development of NICM (biventricular EDV and ESV, LV-EF), 7 with DCM (biventricular EF, ESV, EDV, and LV end-diastolic mass (EDM), and 3 associate with AF (LV-ESV, RV-EF, RV-ESV). Higher EF of both ventricles associate with lower risk of HF and DCM, with biventricular ESV associating with all four cardiac outcomes. Higher values of biventricular EDV associate with lower risk of HF, and DCM. Exploring the associations of these CMR cardiac disease surrogates with non-cardiac traits confirms a strong link with diastolic blood pressure, as well as more specific associations with lung function (LV-ESV), HbA1c (LV-EDM), and type 2 diabetes (LV-SV). CONCLUSIONS: The current paper identifies key CMR measurements that may act as surrogate endpoints for the development of HF (including NICM and DCM) or AF.