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.
Highlights
While coronary artery disease (CAD) occurs in both older men and women, coronary microvascular dysfunction (CMD) is more often present in older women, who often exhibit signs and symptoms of CAD in the absence of obstructive coronary arteries [1]
This study shows that old rats treated with stromal vascular fraction (SVF) cells exhibited improved coronary flow reserve (CFR), regional coronary perfusion, and left ventricular diastolic dysfunction (LVDD) compared to old control and old rats treated with a control cell population
All old groups (OC, old + rat aortic endothelial cells (O+EC), and old + GFP+ SVF cells (O+SVF)) exhibited increased body weight (BW), total ventricular weight (HW), and LV weight compared to young control (YC), but the ratio of HW/BW from old groups with or without treatment was not different from YC
Summary
While coronary artery disease (CAD) occurs in both older men and women, coronary microvascular dysfunction (CMD) is more often present in older women, who often exhibit signs and symptoms of CAD in the absence of obstructive coronary arteries [1]. The incidence of left ventricular diastolic dysfunction (LVDD) increases in women after menopause and leads to heart failure [2]. Cell therapy (using sources such as bone marrow and cardiac tissue) has been utilized in clinical trials to treat CAD and heart failure with moderate success, and this may be a more realistic treatment option for CMD. SVF from adipose tissue has anti-apoptotic, anti-oxidant, anti-inflammatory, immune-modulatory effects via direct immunosuppressive/tolerance-inducing properties [12]. These positive characteristics of SVF has significantly raised the number of ongoing clinical trials using adipose-derived cells as a cell therapy [13]
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