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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.

SUBMITTER: Kelm NQ

PROVIDER: S-EPMC6108481 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Kelm Natia Q NQ Beare Jason E JE Yuan Fangping F George Monika M Shofner Charles M CM Keller Bradley B BB Hoying James B JB LeBlanc Amanda J AJ LeBlanc Amanda J AJ

PloS one 20180824 8

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. There ...[more]

PMID: 30142193

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Project description:BackgroundMicrovascular pathology is one of the main characteristics of diabetic cardiomyopathy; however, the early longitudinal course of diabetic microvascular dysfunction remains uncertain. This study aimed to investigate the early dynamic changes in left ventricular (LV) microvascular function in diabetic pig model using the cardiac magnetic resonance (CMR)-derived quantitative perfusion technique.MethodsTwelve pigs with streptozotocin-induced diabetes mellitus (DM) were included in this study, and longitudinal CMR scanning was performed before and 2, 6, 10, and 16 months after diabetic modeling. CMR-derived semiquantitative parameters (upslope, maximal signal intensity, perfusion index, and myocardial perfusion reserve index [MPRI]) and fully quantitative perfusion parameters (myocardial blood flow [MBF] and myocardial perfusion reserve [MPR]) were analyzed to evaluate longitudinal changes in LV myocardial microvascular function. Pearson correlation was used to analyze the relationship between LV structure and function and myocardial perfusion function.ResultsWith the progression of DM duration, the upslope at rest showed a gradually increasing trend (P = 0.029); however, the upslope at stress and MBF did not change significantly (P > 0.05). Regarding perfusion reserve function, both MPRI and MPR showed a decreasing trend with the progression of disease duration (MPRI, P = 0.001; MPR, P = 0.042), with high consistency (r = 0.551, P < 0.001). Furthermore, LV MPR is moderately associated with LV longitudinal strain (r = - 0.353, P = 0.022), LV remodeling index (r = - 0.312, P = 0.033), fasting blood glucose (r = - 0.313, P = 0.043), and HbA1c (r = - 0.309, P = 0.046). Microscopically, pathological results showed that collagen volume fraction increased gradually, whereas no significant decrease in microvascular density was observed with the progression of DM duration.ConclusionsMyocardial microvascular reserve function decreased gradually in the early stage of DM, which is related to both structural (but not reduced microvascular density) and functional abnormalities of microvessels, and is associated with increased blood glucose, reduced LV deformation, and myocardial remodeling.

Project description:Aims:More than 50% of patients with heart failure have preserved ejection fraction characterized by diastolic dysfunction. The prevalance of diastolic dysfunction is higher in females and associates with multiple comorbidities such as hypertension (HT), obesity, hypercholesterolemia (HC), and diabetes mellitus (DM). Although its pathophysiology remains incompletely understood, it has been proposed that these comorbidities induce systemic inflammation, coronary microvascular dysfunction, and oxidative stress, leading to myocardial fibrosis, myocyte stiffening and, ultimately, diastolic dysfunction. Here, we tested this hypothesis in a swine model chronically exposed to three common comorbidities. Methods and results:DM (induced by streptozotocin), HC (produced by high fat diet), and HT (resulting from renal artery embolization), were produced in 10 female swine, which were followed for 6 months. Eight female healthy swine on normal pig-chow served as controls. The DM + HC + HT group showed hyperglycemia, HC, hypertriglyceridemia, renal dysfunction and HT, which were associated with systemic inflammation. Myocardial superoxide production was markedly increased, due to increased NOX activity and eNOS uncoupling, and associated with reduced NO production, and impaired coronary small artery endothelium-dependent vasodilation. These abnormalities were accompanied by increased myocardial collagen content, reduced capillary/fiber ratio, and elevated passive cardiomyocyte stiffness, resulting in an increased left ventricular end-diastolic stiffness (measured by pressure-volume catheter) and a trend towards a reduced E/A ratio (measured by cardiac MRI), while ejection fraction was maintained. Conclusions:The combination of three common comorbidities leads to systemic inflammation, myocardial oxidative stress, and coronary microvascular dysfunction, which associate with myocardial stiffening and LV diastolic dysfunction with preserved ejection fraction.

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

Publications

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

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