Graduate Student University of Toronto Toronto, Ontario, Canada
Background: Heart failure with preserved ejection fraction (HFpEF) is highly prevalent in patients with ‘vascular’ risk factors such as obesity, hypertension, and type-2 diabetes. Indeed, HFpEF can be characterized by cardiac microvascular dysfunction and impaired diastolic function. However, there is limited understanding of the mechanisms by which these perturbations arise. We posit that these hallmarks of HFpEF originate in Sca1+CD31-CD45-vessel-resident progenitor cells (VRP) which then give rise to dysfunctional vascular cell progeny contributing to the pathogenesis of HFpEF.
METHODS AND RESULTS: To induce HFpEF, male wild-type C57BL/6N mice were fed 60% high-fat diet chow (HFD) plus 0.5 g/L L-NAME in drinking water ad libitum, or normal-chow and -drinking water, for 15-wk. As expected, this two-hit model of obesity [HFD] plus hypertension [L-NAME] model exhibited hallmarks of HFpEF, notably increased body weight [44±1g vs. 30±1g; n=24-27/group; p< 0.0001], cardiac hypertrophy [heart weight to tibia length ratio; 11.1±0.4 mg/mm vs. 8.4±0.2; n=24-27/group; p< 0.0001], increased systolic blood pressure [invasive catheterization; 106±5 mmHg vs. 86±3; n=9-10/group; p< 0.01], diastolic dysfunction [global longitudinal strain -13±1% vs. -17±1%; n=24-27/group; p< 0.01], and impaired glucose tolerance [AUC-GTT; 57,857±6039 vs. 26,649±2667; n=24-27/group; p< 0.0001]. Histological analyses of cardiac CD31+ endothelial cells [per high-powered field] revealed microvascular rarefaction [315±20 cells (36±3% of nuclei) vs. 393±22 (44±2%); n=9-10/group; p< 0.05]. Interestingly, loss of CD31+ microvasculature correlated with the degree of diastolic dysfunction [r=-0.61, p< 0.01]. Similarly, Sca1+CD31-CD45- VRP numbers and proportions were reduced in HFD+L-NAME fed mice [87±10 cells (10±1% of nuclei) vs. 117±9 (13±1%); n=9-10/group; p< 0.05], and these proportions of VRP negatively correlate with global longitudinal strain [r=-0.66, p< 0.01], suggesting a link between reduced VRP numbers and diastolic dysfunction.
Conclusion: These data implicate VRP in the development of HFpEF and identify VRP as a potential therapeutic target in which to treat microvascular dysfunction. Ongoing studies are dissecting the kinetics and mechanisms underlying VRP-mediated diastolic dysfunction.
