Improved diastolic dysfunction and coronary blood flow in aging following stromal vascular fraction therapy

Abstract

In aged female rats and humans, decreased coronary flow contributes to an increased risk of cardiovascular disease. Coronary microvascular disease, caused by damage to the endothelial lining of coronary vessels, significantly alters microcirculation and leads to coronary perfusion deficits. Our past research has shown that tail vein injection of adipose‐derived stromal vascular fractions (SVF) was effective at migrating to the walls of peripheral small vessels and resetting dysregulated vasomotor tone. We hypothesized that i.v. injection of SVF would reverse the coronary microvascular dysfunction caused by aging by incorporating into the coronary microvessels and improving perfusion.MethodsYoung (3 months, n=9) and old (22 months, n=38) female fisher‐344 rats received baseline cardiac vevo measurements. Old rats were then divided into 3 groups: control (no treatment, n=9), negative control (i.v. injection of 6×10(6) endothelial cells (ECs), n=12) and experimental group which received 6×10(6) green fluorescent protein (GFP+) SVF cells (n=9)). Cardiac –vevo measurements were evaluated again at four weeks post injection. The left anterior descending (LAD) coronary arterioles were isolated for microvessel reactivity studies. Immunohistochemistry staining was performed on a subset of hearts.Results(GFP+) SVF cells were engrafted into the myocardium and coronary vasculature four weeks after injection (5.0% +/− 0.9% of total nucleated cells, n=4). Fractional shortening was not different between groups, but left ventricular diastolic function (E/A ratio) was significantly decreased in aged rats compared to young. Importantly, this was rescued after SVF treatment, but not EC injection. Coronary Peak velocity and coronary flow reserve (CFR) of the LAD were improved in old rats receiving SVF therapy vs. old control group. Endothelium‐dependent flow‐mediated relaxation was rescued in all old rats after incubating coronary arterioles with conditioned media (supernatant of rat cardiomyocytes cultured with 5% SVF cells). Only arterioles from SVF treated rats increased myogenic response following conditioned media, suggesting SVF therapy primes the coronary microcirculation to increased dilation in aging. Measures of vasoconstriction (endothelin) were similar between groups. A subset of SVF animals with indwelling telemetry units did not exhibit increased arrhythmias or mortality.Conclusioni.v. injected SVF cells are capable of incorporating into the cardiac peri‐vascular tissue and were shown to transiently improve coronary blood flow (CFR and microvascular vasoreactivity) and diastolic function in a model of advanced age. Importantly this cell therapy did not result in increased rate of arrhythmias or increased mortality. SVF cells provide an autologous cell therapy option for treatment of coronary and cardiac dysfunction in aged population.Support or Funding InformationNIH RO1 AG053585Jewish Heritage Fund for Excellence and the Green's FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.