Purpose: As ageing is associated with slowing of LV relaxation, and HFpEF is predominant in older patients, this study examined the impact of SMTNL1 silencing on cardiac function with increasing age in a murine transgenic model.
Methods: SMTNL1 global KO mice (3- and 12-month old, male and female) were assessed by echocardiography, followed by LV catheterization (PVR 1045, Millar Instruments) and pressure-volume loop measurements to assess the systolic-diastolic and hemodynamic parameters of cardiac function. The background strain 129S6 wildtype (WT) mice served as the control group.
Results: Like young males, aged 12-month old male KO mice developed diastolic dysfunction as evident from increased Tau (12.8±0.6 vs 11.0±0.3 ms, p<0.05), EDP (10.3±1.4 vs 6.7±0.5 mmHg, p=0.05) and EDPVR (0.46±0.03 vs 0.14±0.04, p<0.0001); along with an elevated E/E´ ratio (29.4±1.8 vs 23.2±1.9, p<0.05). However, the female KO group did not develop diastolic dysfunction even at 12-months of age. Although both male and female cohorts showed normal ejection fraction, aged male KO group showed significantly reduced E/A ratio (1.16±0.08 vs 1.56±0.15, p<0.05) in relation to their younger counterparts. Furthermore, with age the total peripheral resistance (25.6±4.5 vs 12.0±0.8 mmHg×min/µl, p<0.05) and the arterial elastance (Ea; 8.7±0.9 vs 4.8±0.9 mmHg/µl, p<0.01) was exacerbated in only male KO animals. Ageing was also associated with increased LV mass and wall thickness along with fibrotic remodelling in the KO group.
Conclusions: We have identified a potentiating effect of age on vascular and cardiac dysfunction in the absence of SMTNL1. The SMTNL1 KO model recapitulates HFpEF clinical phenotypes and represents a novel pre-clinical model to study the aetiology of HFpEF condition, in the absence of any confounding comorbidities. However, the absence of diastolic dysfunction in KO female mice potentially through the protective role of oestrogen requires further study using ovariectomized animals.