Browsing by Author "Neto-Neves, Evandro M."

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    Chronic Embolic Pulmonary Hypertension Caused by Pulmonary Embolism and Vascular Endothelial Growth Factor Inhibition
    (Elsevier, 2017-04) Neto-Neves, Evandro M.; Brown, Mary B.; Zaretskaia, Maria V.; Rezania, Samin; Goodwill, Adam G.; McCarthy, Brian P.; Persohn, Scott A.; Territo, Paul R.; Kline, Jeffrey A.; Emergency Medicine, School of Medicine
    Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively. PE + SU rats exhibited sustained pulmonary hypertension (62 ± 13 and 53 ± 14 mmHg at 3 and 6 weeks, respectively) with reduction of the ventriculoarterial coupling in vivo coincident with a large decrement in peak rate of oxygen consumption during aerobic exercise, respectively. PE + SU produced right ventricular hypokinesis, dilation, and hypertrophy observed on echocardiography, and 40% reduction in right ventricular contractile function in isolated perfused hearts. High-resolution computed tomographic pulmonary angiography and Ki-67 immunohistochemistry revealed abundant lung neovascularization and cellular proliferation in PE that was distinctly absent in the PE + SU group. We present a novel rodent model to reproduce much of the known phenotype of CTEPH, including the pivotal pathophysiological role of impaired vascular endothelial growth factor-dependent vascular remodeling. This model may reveal a better pathophysiological understanding of how PE transitions to CTEPH in human treatments.
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    Comparison of isoflurane and α-chloralose in an anesthetized swine model of acute pulmonary embolism producing right ventricular dysfunction
    (American Association for Laboratory Animal Science, 2015-02) Beam, Daren M.; Neto-Neves, Evandro M.; Stubblefield, William B.; Alves, Nathan J.; Tune, Johnathan D.; Kline, Jeffrey A.; Department of Emergency Medicine, IU School of Medicine
    Pulmonary embolism (PE) is a leading cause of sudden cardiac death, and a model is needed for testing potential treatments. In developing a model, we compared the hemodynamic effects of isoflurane and α-chloralose in an acute swine model of PE because the choice of anesthesia will likely affect the cardiovascular responses of an animal to PE. At baseline, swine that received α-chloralose (n = 6) had a lower heart rate and cardiac output and higher SpO2, end-tidal CO2, and mean arterial pressure than did those given isoflurane (n = 9). After PE induction, swine given α-chloralose compared with isoflurane exhibited a lower heart rate (63 ± 10 compared with 116 ± 15 bpm) and peripheral arterial pressure (52 ± 12 compared with 61 ± 12 mm Hg); higher SpO2 (98% ± 3% compared with 95% ± 1%), end-tidal CO2 (35 ± 4 compared with 32 ± 5), and systolic blood pressure (121 ± 8 compared with 104 ± 20 mm Hg); and equivalent right ventricular:left ventricular ratios (1.32 ± 0.50 compared with 1.23 ± 0.19) and troponin I mean values (0.09 ± 0.07 ng/mL compared with 0.09 ± 0.06 ng/mL). Isoflurane was associated with widely variable fibrinogen and activated partial thromboplastin time. Intraexperiment mortality was 0 of 6 animals for α-chloralose and 2 of 9 swine for isoflurane. All swine anesthetized with α-chloralose survived with sustained pulmonary hypertension, RV-dilation-associated cardiac injury without the confounding vasodilatory or coagulatory effects of isoflurane. These data demonstrate the physiologic advantages of α-chloralose over isoflurane for anesthesia in a swine model of severe submassive PE.
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    The resistance of swine blood clots to alteplase-induced thrombolysis in vitro is concentration-dependent
    (Elsevier, 2021) Neto-Neves, Evandro M.; Beam, Daren M.; Kline, Jeffrey A.; Emergency Medicine, School of Medicine
    Background: Swine have been used as a large animal translational research model to investigate the effectiveness of fibrinolytic agents. However, swine thrombi have different characteristics than human thrombi, which may confer more resistance to fibrinolysis. Methods: In this study, we performed an in-vitro clot lysis assay to compare both human and swine blood clots lysis induced by alteplase, a recombinant tissue plasminogen-activator agent. Human and swine whole blood were allowed to clot for 3 ​h at 37 ​°C. Increasing concentrations of alteplase (250–580,000 IU/mL) or phosphate-buffered saline (PBS, pH 7.4) were added into the clots. Clot lysis was determined by calculating the difference between the clot mass pre- and post-lysis. Results: At low alteplase concentrations (250–2000 IU/mL) we observed significantly less swine blood clot lysis (14 ​± ​1.7% - 35 ​± ​4.9%) compared to the lysis found to human blood clots (52 ​± ​4.8% - 68 ​± ​3.3%, ∗p ​< ​0.05). In contrast, we did not find lysis differences between human and swine clots at higher alteplase concentrations (5000–580,000 IU/mL). Conclusions: In conclusion, our results suggest that the swine clot resistance to alteplase-induced thrombolysis is concentration-dependent. A high concentration of alteplase allows equivalent thrombolysis of swine and human blood clots in vitro.