APOE ε4 carriage associates with improved myocardial performance in older age

ABSTRACT Introduction Although APOE ε 4 allele carriage confers a risk of coronary disease, its persistence in human populations might be explained by certain survival advantages (antagonistic pleiotropy). Hypothesis Combining data from three British cohorts–1946 National Survey of Health and Development (NSHD), Southall and Brent Revised (SABRE) and UK Biobank–we explored whether APOE ε 4 carriage associates with beneficial or unfavorable left ventricular (LV) structural and functional parameters by echocardiography and cardiovascular magnetic resonance (CMR) in older age. Methods Based on the presence of APOE ε 4, genotypes were divided into: APOE ε 4 (ε2ε4, ε3ε4, ε 4 ε 4) and non- APOE ε 4 carriers. Echocardiographic data included: LV ejection fraction, E/e’, systolic and diastolic posterior wall and interventricular septal thickness (LVPWT s/d , IVS s/d ), LV mass and the ratio of the LV stroke volume to the LV myocardial volume called myocardial contraction fraction (MCF). CMR data additionally included longitudinal and radial peak diastolic strain rates (PDSR). Generalized linear models explored associations between APOE ε 4 genotypes as exposures and echocardiographic/CMR biomarkers as outcomes. As APOE genotype is a genetic instrumental variable (unconfounded), Model 1 was unadjusted; Model 2 was adjusted for factors associated with the outcome (age, sex, and socio-economic position) to yield more precise estimates; and subsequent models were individually adjusted for mediators (body mass index, cardiovascular disease [CVD], high cholesterol and hypertension) to explore mechanistic pathways. Results 35,568 participants were included. Compared to the non- APOE ε 4 group, APOE ε 4 carriers had similar cardiac echocardiographic phenotypes in terms of LV EF, E/e’, LVPWT s/d , IVS s/d and LV mass but had a 4% higher MCF (95% confidence interval [CI]: 1–7%, p =0.016) which persisted in Model 2 (95% CI 1–7%, p =0.008) but was attenuated to 3% after adjustment for CVD, diabetes and hypertension (all 95% CI 0–6%; all p <0.070). This was replicated in UK Biobank using CMR data, where APOE ε 4 carriers had a 1% higher MCF (95% CI 0-1%, p =0.020) which was attenuated only after adjusting for BMI or diabetes. Conclusions APOE ε 4 carriage associates with improved myocardial performance in older age resulting in greater LV stroke volume generation per 1 mL of myocardium and better longitudinal strain rates compared to non APOE ε 4 carriers. This potentially favorable cardiac phenotype adds to the growing number of reported survival advantages attributed to APOE ε4 carriage that might collectively explain its persistence in humans.