Objective: Discrete morphologic, enzymatic and functional changes in skeletal muscle mitochondria have been demonstrated in patients with peripheral arterial disease (PAD). We examined mitochondrial respiration in the gastrocnemius muscle of nine patients (10 legs) with advanced PAD and in nine control patients (nine legs) without evidence of PAD. Methods: Mitochondrial respiratory rates were determined with a Clark electrode in an oxygraph cell containing saponin-skinned muscle bundles. Muscle samples were obtained from the anteromedial aspect of the gastrocnemius muscle, at a level 10 cm distal to the tibial tuberosity. Mitochondria respiratory rate, calculated as nanoatoms of oxygen consumed per minute per milligram of noncollagen protein, were measured at baseline (V 0 ), after addition of substrates (malate and glutamate; (V SUB ), after addition of adenosine diphosphate (ADP) (V ADP ), and finally, after adenine nucleotide translocase inhibition with atractyloside (V AT ). The acceptor control ratio, a sensitive indicator of overall mitochondrial function, was calculated as the ratio of the respiratory rate after the addition of ADP to the respiratory rate after adenine nucleotide translocase inhibition with atractyloside (V ADP / V AT ). Results: Respiratory rate in muscle mitochondria from patients with PAD were not significantly different from control values at baseline (0.31 ؎ 0.06 vs 0.55 ؎ 0.12; P ؍ .09), but V sub was significantly lower in patients with PAD compared with control subjects (0.43 ؎ 0.07 vs 0.89 ؎ 0.20; P < .05), as was V ADP (0.69 ؎ 0.13 vs 1.24 ؎ 0.20; P < .05). Respiratory rates after atractyloside inhibition in patients with PAD were no different from those in control patients (0.47 ؎ 0.07 vs 0.45 ؎ P ؍ .08). Compared with control values, mitochondria from patients with PAD had a significantly lower acceptor control ratio (1.41 ؎ 0.10 vs 2.90 ؎ 0.20; P < .001). Conclusion: Mitochondrial respiratory activity is abnormal in lower extremity skeletal muscle in patients with PAD. When considered in concert with the ultrastructural and enzymatic abnormalities previously documented in mitochondria of chronically ischemic muscle, these data support the concept of defective mitochondrial function as a pathophysiologic component of PAD.
Phosphorus 31 MRS provides the first direct evidence of defective energy metabolism in the mitochondria of claudicating calf muscle. This defect appears to be independent of both arterial flow and the severity of occlusive disease in patients with mild to moderate claudication. Coupled with documented ultrastructural and DNA abnormalities in the mitochondria of claudicating skeletal muscle, these data provide evidence for a secondary cause of muscle dysfunction in intermittent claudication.
Reverse remodeling with reduced systolic wall stress and improved adrenergic signaling can be achieved by passive external support that does not generate diastolic constriction. This approach may prove useful in the treatment of chronic heart failure.
Surgical outcomes in heterotaxy patients are improving in the current era. The risk for operative mortality and attrition is highest between the first and second stage palliation procedures. Significant atrioventricular valve regurgitation and obstructed TAPVR remain risk factors for RAI mortality. Survivors are doing well with no activity restrictions, although LAI patients maintain a higher proclivity of sinus node dysfunction.
Objective
Ventricular kinetic energy measurements may provide a novel imaging biomarker of declining ventricular efficiency in patients with repaired Tetralogy of Fallot (rTOF). Our purpose was to assess differences in ventricular kinetic energy (KE) with four-dimensional (4D) Flow MRI between patients with rTOF and healthy volunteers.
Methods
Cardiac MR (CMR), including 4D Flow MRI, was performed at rest in 10 subjects with rTOF and nine healthy volunteers using clinical 1.5T and 3T MRI scanners. Right and left ventricular kinetic energy (KERV and KELV), main pulmonary artery flow (QMPA), and aortic flow (QAO) were quantified using 4D Flow MRI data. Right and left ventricular size and function were measured using standard CMR techniques. Differences in peak systolic KERV and KELV in addition to the QMPA/KERV and QAO/KELV ratios between groups were assessed. KE indices were compared to conventional CMR parameters.
Results
Peak systolic KERV and KELV were higher in rTOF subjects (6.06±2.27mJ and 3.55±2.12mJ, respectively) than healthy volunteers (5.47±2.52mJ and 2.48±0.75mJ, respectively) but not statistically significant (p= .65 and p= .47, respectively). The QMPA/KERV and QAO/KELV ratios were lower in rTOF subjects (7.53±5.37mL/(cycle-mJ) and 9.65±6.61mL/(cycle-mJ), respectively) than healthy volunteers (19.33±18.52mL/(cycle-mJ) and 35.98±7.66mL/(cycle-mJ), respectively; p< .05). QMPA/KERV and QAO/KELV were weakly correlated to ventricular size and function.
Conclusions
Greater ventricular KE is necessary to generate flow in the pulmonary and aortic circulations in rTOF. Quantification of ventricular KE in patients with rTOF is a new observation. Future studies are needed to determine if changes in ventricular KE can provide earlier evidence of ventricular dysfunction and guide future medical and surgical interventions.
SummaryHere, we describe the NeoThy humanized mouse model created using non-fetal human tissue sources, cryopreserved neonatal thymus and umbilical cord blood hematopoietic stem cells (HSCs). Conventional humanized mouse models are made by engrafting human fetal thymus and HSCs into immunocompromised mice. These mice harbor functional human T cells that have matured in the presence of human self-peptides and human leukocyte antigen molecules. Neonatal thymus tissue is more abundant and developmentally mature and allows for creation of up to ∼50-fold more mice per donor compared with fetal tissue models. The NeoThy has equivalent frequencies of engrafted human immune cells compared with fetal tissue humanized mice and exhibits T cell function in assays of ex vivo cell proliferation, interferon γ secretion, and in vivo graft infiltration. The NeoThy model may provide significant advantages for induced pluripotent stem cell immunogenicity studies, while bypassing the requirement for fetal tissue.
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