Adipose-derived cells improve left ventricular diastolic function and increase microvascular perfusion in advanced age

Abstract

An early manifestation of coronary artery disease in advanced age is the development of microvascular dysfunction leading to deficits in diastolic function. Our lab has previously shown that epicardial treatment with adipose-derived stromal vascular fraction (SVF) preserves microvascular function following coronary ischemia in a young rodent model. Follow-up studies showed intravenous (i.v.) delivery of SVF allows the cells to migrate to the walls of small vessels and reset vasomotor tone. Therefore we tested the hypothesis that the i.v. cell injection of SVF would reverse the coronary microvascular dysfunction associated with aging in a rodent model. Fischer 344 rats were divided into 4 groups: young control (YC), old control (OC), old + rat aortic endothelial cells (O+EC) and old + GFP+ SVF cells (O+SVF). After four weeks, cardiac function and coronary flow reserve (CFR) were measured via echocardiography, and hearts were explanted either for histology or isolation of coronary arterioles for vessel reactivity studies. In a subgroup of animals, microspheres were injected during resting and dobutamine-stimulated conditions to measure coronary blood flow. GFP+ SVF cells engrafted and persisted in the myocardium and coronary vasculature four weeks following i.v. injection. Echocardiography showed age-related diastolic dysfunction without accompanying systolic dysfunction; diastolic function was improved in old rats after SVF treatment. Ultrasound and microsphere data both showed increased stimulated coronary blood flow in O+SVF rats compared to OC and O+EC, while isolated vessel reactivity was mostly unchanged. I.v.-injected SVF cells were capable of incorporating into the vasculature of the aging heart and are shown in this study to improve CFR and diastolic function in a model of advanced age. Importantly, SVF injection did not lead to arrhythmias or increased mortality in aged rats. SVF cells provide an autologous cell therapy option for treatment of microvascular and cardiac dysfunction in aged populations.

Immune Dysregulation in HFpEF: A Target for Mesenchymal Stem/Stromal Cell Therapy

“…We hypothesize this may be a consequence of decreased Th1 influx into the heart, as IFN-γ producing cells have been shown to support fibrosis development by direct contact with cardiac fibroblasts [75]. Finally, intravenous (IV) infusion of stromal vascular fraction (SVF) was also shown to reduce diastolic dysfunction and LV collagen content at 4 weeks after treatment in an aging rat model [98]. Similar to data regarding T-cell antagonism, reports regarding the effects of MSCs on LVH are conflicting, spanning from minimal [98] to no effect [97].…”

“…Finally, intravenous (IV) infusion of stromal vascular fraction (SVF) was also shown to reduce diastolic dysfunction and LV collagen content at 4 weeks after treatment in an aging rat model [98]. Similar to data regarding T-cell antagonism, reports regarding the effects of MSCs on LVH are conflicting, spanning from minimal [98] to no effect [97].…”

Adipose‐resident myeloid‐derived suppressor cells modulate immune cell homeostasis in healthy mice

“…CD11b + CD301 À Ly6C Hi Ly6G À and Ly6C Low Ly6G + cells are in AT from metabolically healthy mice Previous work in our laboratory has examined the therapeutic value of the AT SVF in improving vascular function. [16][17][18] In one study the SVF isolate lost many of its beneficial effects when the CD11b + cells were depleted. 17 Further characterization of these therapeutically relevant CD11b + cells found that approximately 45% of were also Gr1 + .…”

Evaluation of Coronary Flow Reserve After Myocardial Ischemia Reperfusion in Rats

“…CFR is calculated as the ratio of the peak flow velocity during stress (Dobutamine) to the resting flow velocity (measured prior to Dobutamine infusion) 8 . CFR was 2.1 ± 0.35 in young rats before the IR surgery ( Figure 3B) but significantly reduced (1.1 ± 0.25) after 72 h of the IR surgery, even though the resting LAD coronary artery velocity was higher in these rats compared to data obtained before IR surgery ( Figure 3C).…”

“…Transthoracic Doppler echocardiography is a noninvasive tool which allows us to study coronary artery flow velocity and CFR 5 . CFR represents the ratio of maximal coronary blood flow to the resting coronary blood flow 8 . During the stress challenge, a normal heart increases coronary blood flow up to four times above the resting value.…”