Background The sarcoplasmic reticulum calcium ATPase (SERCA2a) is an important molecular regulator of contractile dysfunction in heart failure. Gene transfer of SERCA2a mediated by molecular cardiac surgery with recirculating delivery (MCARD) is a novel and clinically translatable strategy. Methods Ischemic heart failure was induced by ligation of OM1 and OM2 in 14 sheep. Seven sheep underwent MCARD-mediated AAV1-SERCA2a delivery 4 weeks after myocardial infarction, and seven sheep served as untreated controls. Magnetic resonance imaging—based mechanoenergetic studies were performed at baseline, 3 weeks, and 12 weeks after infarction. Myocyte apoptosis was quantified by Tdt-mediated nick-end labeling assay. Myocyte cross-sectional area and caspase-8 and caspase-9 activity was measured with imaging software, specific fluorogenic peptides, and immunohistochemistry. Results MCARD-mediated AAV1-SERCA2a gene delivery resulted in robust cardiac-specific SERCA2a expression and stable improvements in global and regional contractility. There were significantly higher stroke volume index, left ventricular fractional thickening, and ejection fraction at 12 weeks in the MCARD group than in the control group (30 ± 3 vs 21 ± 2 mL/m2; 12% ± 5% vs 3% ± 3%; and 43 ± 4 vs 32 ± 4, respectively, all p < 0.05). Apoptotic myocytes were observed more frequently in the control group than in the MCARD-SERCA2a group (0.57.2 ± 0.16 AU vs 0.32.4 ± 0.08 AU, p < 0.05). MCARD-SERCA2a also resulted in decreased caspase-8 and caspase-9 expression and decreased myocyte area in the border zone of transgenic sheep compared with control sheep (14.6% ± 1.2% vs 2.9% ± 0.7%; 18.2% ± 1.9% vs 8.6% ± 1.4%; and 102.1 ± 3.8 μm2 vs 88.1 ± 3.6 μm2, all p < 0.05). Conclusions MCARD-mediated SERCA2a delivery results in robust cardiac specific gene expression, improved contractility, and a decrease in both myocyte apoptosis and myocyte hypertrophy.
The article reviews the problem of hemorrhagic transformation (HT) of ischemic stroke. The frequency and relevance of this complication in clinical practice is high considering the widespread implementation of cerebral recanalization methods: intravenous thrombolytic therapy and intravascular thromboembolectomy. The etiology and pathogenesis, as well as alternative mechanisms underlying the development of HT are also discussed. The probability of HT increases in case of extensive cerebral ischemia commonly associated with cardiac embolism. The role of spontaneous and medication-induced arterial recanalization of cerebral arteries in the genesis HT is discussed. In particular, it is noted that arterial recanalization is not an essential factor for the occurrence of HT in cerebral infarction. The severity of HT is determined by the duration and degree of cerebral ischemia. There is a need for a targeted search for HT predictors. The classification of types and criteria of HT are presented. The risk factors and scales used to predict HT are studied. Risk factors for HT are combined into several groups: clinical, laboratory, genetic, neuroimaging. Their comparative analysis is carried out and practical significance is estimated.
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