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.

Background Sub-Saharan Africa (SSA) faces a critical shortage of pediatric surgical providers. International partnerships can play an important role in pediatric surgical capacity building but must be ethical and sustainable. Objective The purpose of this study is to perform a scoping literature review of international pediatric surgery partnerships in SSA from 2009 to 2019. We aim to categorize and critically assess past partnerships to aid in future capacity-building efforts. Methods We performed a scoping literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) guidelines. We searched the PubMed and Embase databases for articles published from 2009 to 2019 using 24 keywords. Articles were selected according to inclusion criteria and assessed by two readers. Descriptive analyses of the data collected were conducted in Excel. Results A total of 2376 articles were identified. After duplicates were removed, 405 articles were screened. In total, 83 articles were assessed for eligibility, and 62 were included in the review. The most common partnership category was short-term surgical trip (28 articles, 45%). A total of 35 articles (56%) included education of host country providers as part of the partnership. Only 45% of partnerships included follow-up care, and 50% included postoperative outcomes when applicable. Conclusions To increase sustainability, more partnerships must include education of local health-care providers, and short-term surgical trips must be integrated into long-term partnerships. More partnerships need to report postoperative outcomes and ensure follow-up care. Educating peri-operative providers, training general surgeons in common pediatric procedures, and increasing telehealth use are other goals for future partnerships.

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

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.