Health and social inequalities in childhood associate with left ventricular diastolic dysfunction: A life-course EWAS of the 1946 Birth Cohort

Background: and purpose: Left ventricular diastolic dysfunction (LVDD) is a key pathophysiological mechanism in heart failure with preserved ejection fraction (HFpEF) but its environmental determinants are poorly understood. We undertook a life-course environment-wide association study (EWAS) of LVDD to test a variety of environmental and biomedical exposures in a high-throughput manner. Methods: Participants were from the Medical Research Council (MRC) National Survey of Health and Development (NSHD, the 1946 British Birth cohort) who had echocardiographic data recorded at 60-64 years. LVDD (outcome) was defined as per the American Society of Echocardiography LVDD guidelines. 255 life-course factors (exposures) were investigated for their association with LVDD. Significant factors were identified using a logistic regression model adjusting for sex, body mass index and socioeconomic position (SEP, dichotomised as manual or non-manual) at a false discovery rate of 5%. Interactions between individual exposures were appraised using exposome correlation globes and matrices. Results: 1616 Participants were included (50.4% men, 21.4% with LVDD) and 21 factors were associated with LVDD (p≤0.05) after adjustment. Better childhood cognition (odds ratio 0.86 [95% confidence interval 0.75-0.99]), home conditions (0.90 [0.83-0.97]) and paternal SEP (0.75 [0.56-0.99]) were associated with less LVDD, while childhood home crowding (1.24 [1.09-1.41]), adult consumption of processed pork (1.28 [1.05-1.58]) and sugar (1.24 [1.02-1.50]), and adult systolic hypertension (1.22 [1.06-1.39]) were associated with more LVDD. Conclusion: We have unmasked and rediscovered several exposures throughout the life-course that either protect against or promote, the emergence of LVDD in later life, in particular cognition, housing conditions and diet. Addressing health and social inequalities in childhood might therefore potentially help combat the emerging epidemic of HFpEF.