Early life stress Induces age-dependent cardiac dysfunction in exposed parents and in their offspring

Abstract Introduction Early life stress (ELS) in childhood due to physical or sexual violence, parental neglect, or trauma has been recently associated with an increased risk of cardiovascular disease in later life. The mechanisms linking ELS to cardiovascular impairment remain unexplored. Moreover, it is also unknown whether parental ELS can be transmitted to the offspring. Purpose We investigate the effects of ELS on cardiac function in exposed parents and in their offspring, across 3 generations. Methods We used a mouse model of ELS (MSUS) which mimics the exposure to traumatic experiences during childhood in humans. In this model, mouse pups (F1) were separated from their mother (F0) unpredictably each day for 3 hours from postnatal day 1 (PND1) to PND14. During separation, dams were exposed to an additional unpredictable stressor (forced swim or tube restraint). From PND15, mice were raised normally until adulthood. Echocardiographic assessment (Vevo 3100, Visualsonics) was performed at 6, 12 and 18 months both in the exposed animals (F0) as well as in their offspring (F1) and grand-offspring (F2). Both male and female mice were studied. RNA sequencing (RNAseq) was used in LV specimens from MSUS mice to unveil transcriptional changes. In vitro experiments in mouse adult cardiomyocytes from control and MSUS mice were performed to investigate the function of top-ranking genes. Finally, MSUS mice underwent environmental enrichment (cages containing running wheels, maze) to investigate any rescuing effect on cardiac function. Results MSUS mice (F0) displayed increased LV mass, impaired diastolic function, myocardial fibrosis and lung congestion. A time-dependent worsening of cardiac performance was observed from 6 to 18 months, both in males and females. The MSUS offspring did not show changes of cardiac function at 6 months, however diastolic dysfunction and lung congestion were observed at 12 and 18 months (Fig. 1). A similar impairment of cardiac function was observed in the MSUS grand-offspring (F2). Of interest, 6-week exposure to an environmental enrichment protocol was able to improve LV mass, diastolic function and myocardial performance in 12 months-old MSUS mice. RNA sequencing unveiled a marked dysregulation of gene transcripts in MSUS hearts vs controls. A profound change of the transcriptional landscape was also found in the heart of F1 and F2 MSUS mice. Bone morphogenetic protein 10 (BMP10) was identified as the top-ranking transcript and was consistently upregulated across MSUS generations (F1 and F2, Fig. 1). Experiments in adult cardiomyocytes confirmed BMP10 upregulation. Of interest, environmental enrichment was able to rewire most of transcriptional changes with a pronounced effect on BMP10 levels (Fig. 2). Conclusions we show for the first time that ELS induces a transgenerational transmission of cardiac phenotypic alterations which can be rescued by stress mitigation strategies.