Adipose Stromal Vascular Fraction Cells Improve Coronary and Cardiac Physiology in the Aged Female Heart

Abstract

Over 50% of adult women presenting with symptoms of ischemic heart disease have “clear” coronary artery angiograms. Additional testing indicates coronary microvascular dysfunction, contributing to the coronary perfusion deficits in these women. Current therapies for this condition, called microvascular angina, are relatively ineffective. Our previous research demonstrated that tissue‐resident macrophages within the therapeutic cell preparation derived from the stromal vascular fraction (SVF) of adipose tissue improved peripheral small artery function. Delivered intravascularly, these SVF‐derived macrophages migrate to the walls of small vessels and reset vasomotor tone. Therefore, we hypothesized that i.v. delivery of SVF cells can reverse coronary microvascular dysfunction. Using the aged female rat heart (22 mos. of age) as a model of coronary microvascular dysfunction without coronary artery involvement, combined with high‐resolution ultrasound and telemetry, we evaluated cardiac function and coronary flow reserve (CFR) in aged animals receiving fluorescently tagged GFP+ SVF cells from syngeneic young rats (6 × 106 cells/rat) via the tail vein at one‐week and four‐weeks post‐injection. At the time of explant, the location of injected SVF cells was determined via confocal microscopy, and isolated coronary arteriole preparations were used to evaluate vasoactivity. Injected GFP+ SVF cells had incorporated into the coronary vasculature one‐week post‐injection and remained there at 4 weeks. While coronary blood flow was improved in animals receiving the cell therapy, vasoreactivity of isolated arterioles to flow, pressure, bradykinin, and endothelin was unaffected. Measures of heart function such as maximal cardiac output, percent heart rate increase, and left ventricular diameter and volume during diastole ‐ which are all compromised in aged animals ‐ were significantly improved in response to a dobutamine challenge compared to pre‐SVF measurements. The cell therapy did not lead to arrhythmias or increased mortality. Our findings indicate that intravenously‐delivered adipose SVF cells disseminate to the aging heart and incorporate into the microvascular wall and perivascular spaces of the coronary vasculature. The presence of the therapeutic cells in the heart is associated with improved coronary perfusion and concomitant cardiac function.Support or Funding InformationJewish Heritage Fund for Excellence