Heritable heart failure traits in mice undergoing early life stress

Abstract Introduction Adverse childhood experiences, known as early life stress (ELS), are associated with increased cardiovascular disease risk in later life, yet the underlying mechanisms remain elusive. Recent evidence indicates that parental life experiences can be transmitted to the offspring. Whether ELS exerts transgenerational effects on the heart is unknown. Purpose To investigate the effects of ELS on cardiac structure and function in exposed parents and in their offspring, across 3 generations. Methods We used a mouse model of ELS (MSUS) that mimics the exposure to traumatic experiences during childhood in humans. 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 by being subjected to either, a forced swim (18°C water for 5 minutes) or a 20-minute physical tube restraint, anytime (unpredictably) during the 3 hours. From PND15, mice are left undisturbed with their mother until PND21, are then raised normally until adulthood. Control litters were raised normally. A high-resolution Micro-Ultrasound System (Vevo 3100, Visualsonics) was used for the echocardiographic assessment at 6, 12 and 18 months both in the exposed animals (F0) as well as in their offspring (F1) and grandoffspring (F2). Both male and female mice were studied. Heart weight/tibia length and left ventricle weight/tibia length were used to assess cardiac mass while myocardial fibrosis was assessed by Masson's Trichrome and Picriosirius Red stainings. Lung congestion was assessed as lung wet/dry weight ratio. Single cell RNA sequencing (scRNAseq) was used in LV specimens from MSUS mice to unveil cell-specific transcriptional changes. Finally, MSUS mice underwent environmental enrichment (cages containing running wheels, maze) to investigate any rescuing effect on cardiac function. Results F1 mice 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. ScRNAseq unveiled dysregulation of transcriptional programs underlying inflammation and lipotoxicity in the cardiomyocyte and endothelial cell clusters. 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. A similar impairment of cardiac function was observed in the MSUS grandoffspring (F3). Of interest, 6-week exposure to an environmental enrichment protocol was able to improve LV mass, diastolic function and lung congestion in 12 months-old MSUS mice. Conclusions ELS induces a transgenerational transmission of cardiac phenotypic alterations which can be rescued by EE. Our results shed light on the potential role of ELS on heart failure development and potential mitigation strategies.