Characterizing the Causal Pathway From Childhood Adiposity to Right Heart Physiology and Pulmonary Circulation Using Lifecourse Mendelian Randomization

Abstract

Background: Observational epidemiological studies have reported an association between childhood adiposity and altered cardiac morphology and function in later life. However, whether this is due to a direct consequence of being overweight during childhood has been difficult to establish, particularly as accounting for other measures of body composition throughout the lifecourse can be exceptionally challenging.

Methods and results: In this study, we used human genetics to investigate this using a causal inference technique known as lifecourse Mendelian randomization. This approach allowed us to evaluate the effect of childhood body size on 11 measures of right heart and pulmonary circulation independent of other anthropometric traits at various stages in the lifecourse. We found strong evidence that childhood body size has a direct effect on an enlarged right heart structure in later life (eg, right ventricular end-diastolic volume: β=0.24 [95% CI, 0.15-0.33]; P=3×10^-7) independent of adulthood body size. In contrast, childhood body size effects on maximum ascending aorta diameter attenuated upon accounting for body size in adulthood, suggesting that this effect is likely attributed to individuals remaining overweight into later life. Effects of childhood body size on pulmonary artery traits and measures of right atrial function became weaker upon accounting for adulthood fat-free mass and childhood height, respectively.

Conclusions: Our findings suggest that, although childhood body size has a long-term influence on an enlarged heart structure in adulthood, associations with the other structural components of the cardiovascular system and their function may be largely attributed to body composition at other stages in the lifecourse.

Keywords: Mendelian randomization; cardiac physiology; childhood adiposity; lifecourse epidemiology; vascular structure.

Figure 1. Schematic diagrams depicting different scenarios whereby childhood adiposity may exert an effect on cardiac outcomes in adulthood using a lifecourse Mendelian randomization approach.

A, Univariable Mendelian randomization was conducted to estimate the “total effect” of childhood body size on cardiac outcomes in adulthood. B, Multivariable Mendelian randomization was subsequently applied to estimate “direct effects” of childhood body size on cardiac outcomes (ie, an effect independent of adulthood body size), as well as simultaneously estimating (C) “indirect effects,” which are mediated along the causal pathway involving adulthood body size.

Figure 2. Forest plots illustrating (A) univariable and (B) multivariable Mendelian randomization effect estimates of childhood and adult body size on measures of right heart structure and function.

Estimates for childhood (blue) and adult (orange) body size per change in body size category with their corresponding 95% CIs. The data underlying these figures can be found in Table S4.

Figure 3. Forest plots illustrating (A) univariable and (B) multivariable Mendelian randomization effect estimates of childhood and adult body size on measures of the pulmonary artery, the thoracic aorta, and their ratio.

Estimates for childhood (blue) and adult (orange) body size per change in body size category with their corresponding 95% CIs. The data underlying these figures can be found in Table S4.