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Diastolic dysfunction and HFpEF characteristics are exacerbated with ageing in smoothelin-like 1 (SMTNL1)-deficient mice

Session Rapid Fire 1 - Basic Science

Speaker Megha Murali

Congress : Heart Failure 2019

  • Topic : basic science
  • Sub-topic : Basic Science - Cardiac Diseases:Heart Failure
  • Session type : Rapid Fire Abstracts
  • FP Number : 8

Authors : M Murali (Calgary,CA), D Belke (Calgary,CA), M Chappellaz (Calgary,CA), WC Cole (Calgary,CA), JA Macdonald (Calgary,CA)

Authors:
M Murali1 , D Belke2 , M Chappellaz1 , WC Cole3 , JA Macdonald1 , 1University of Calgary Foothills Hospital, Department of Biochemistry & Molecular Biology - Calgary - Canada , 2University of Calgary Foothills Hospital, Department of Cardiac Sciences - Calgary - Canada , 3University of Calgary Foothills Hospital, Department of Physiology & Pharmacology - Calgary - Canada ,

On behalf: Libin Cardiovascular Institute of Alberta, Canada

Citation:

Background: Heart failure with preserved ejection fraction (HFpEF) has gained clinical prevalence with ~1% incidence increase per year. Clinical evidence associates HFpEF with endothelial inflammation and microvascular dysfunction, which in turn drive pathologic cardiac remodelling. With a highly comorbid HFpEF patient population and a lack of knowledge about the underlying pathophysiology, no therapeutics are yet available for improving the outcomes of HFpEF patients. Our group revealed a novel impact of the smoothelin-like 1 (SMTNL1) protein which when subjected to genetic deletion drives dramatic alterations in endothelial function and cardiovascular (CV) performance. Of note, previous cardiac hemodynamic profiling show that young male SMTNL1 knockout (KO) mice developed diastolic dysfunction as evident from increased end diastolic pressure (EDP), left ventricular (LV) relaxation time (Tau) and steeper end diastolic pressure-volume relationship (EDPVR).
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.

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