LAUSR

Diastolic dysfunction is a core characteristic of heart failure with preserved ejection fraction (HFpEF), which accounts for half of all HF cases. Our group revealed a novel impact of the smoothelin-like 1 (SMTNL1) protein which when subjected to genetic deletion drives alterations in endothelial and cardiovascular performances. Of note, previous cardiac hemodynamic profiling showed that young male SMTNL1 knockout (KO) mice developed diastolic dysfunction as evidenced by increased end diastolic pressure (EDP), left ventricular relaxation time constant (Tau) and steeper end diastolic pressure-volume relationship (EDPVR). A majority of HFpEF patients are post-menopausal women, so this study examined the impact of SMTNL1 silencing on endothelial and cardiac function with increasing age in a novel female murine model. The cardiac function of SMTNL1 global KO mice (3-, 12- and 18-month old, male and female) was assessed by echocardiography and pressure-volume loop. Unlike young males, 3-month old female KO mice did not develop diastolic dysfunction. However, ageing provided progressive impairment of diastolic function in female KO mice with increased EDP (8.4±1.1 vs 12.2±0.8 mmHg, p<0.02) and EDPVR (0.22±0.05 vs 0.51±0.05, p=0.02) at 18 months; an elevated E/E′ (20.8±1.6 vs 28.3±2.2, p=0.02) and decreased E′/A′ (1.49±0.19 vs 0.97±0.14, p<0.05) at 12 months in comparison to their WT counterparts, along with a normal ejection fraction (>60%) for all age groups. Furthermore, while flow-mediated dilation was continuously impaired in male KO cohorts from 3-month age, female KO showed impairment only at 12-months. Aging was also associated with altered cardiac morphology and fibrotic levels in the aged female KO cohort. Taken together, we have identified pathophysiologic effects of SMTNL1 silencing on vascular and cardiac function with ageing in female mice. The SMTNL1 KO model for the first time recapitulates the sex dimorphic onset of diastolic dysfunction that is central to HFpEF clinical phenotypes and represents a novel preclinical model to study the etiology of the HFpEF condition. Furthermore, the absence of diastolic dysfunction in KO female mice until post-menopausal age reveals a protective role of female sex hormones and warrants further study.