Yan Z, Orellana M, Alarcon D, German R A, Marcillo A E, Pantelis T, Nash M S, Guest J D, McMillan D, Szeto A, Mendez A J, Muir W W, Hamlin R L, Ganzer P D
Department of Biomedical Engineering, University of Miami, Coral Gables, Florida, United States.
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, United States.
bioRxiv. 2025 Aug 28:2025.08.24.671979. doi: 10.1101/2025.08.24.671979.
Cardiovascular dysfunction significantly contributes to morbidity and mortality following cervical spinal cord injury (SCI). Unfortunately, only a limited number of preclinical models have been developed for investigating cardiovascular dysfunction following cervical SCI. Furthermore, the broader consequences of cervical SCI on aerobic capacity and muscle endurance during physiological stress testing also remains understudied preclinically. Therefore, in this study we assessed potential deficits across multiple physiological systems in a rat model of cervical SCI using a battery of stress tests. Female Sprague-Dawley rats (n = 20) received either a C8 midline contusion (cSCI) or laminectomy alone as a control (LAM). Exercise stress testing was conducted to evaluate cardiorespiratory fitness and recovery using a metabolic treadmill, or forelimb fitness using the isometric pull task. Orthostatic stress testing and pharmacological stress testing were also performed to more directly challenge the cardiovascular system. Our findings demonstrate a decline in aerobic fitness in cSCI rats, as evidenced by dysregulated excess post-exercise oxygen consumption. cSCI rats also exhibited impaired muscle endurance compared to LAM. During orthostatic stress testing, 70% of cSCI rats experienced an approximately 25 mmHg decrease in systolic blood pressure and 20 mmHg decrease in diastolic blood pressure, in addition to modest but significant decreases in heart rate, myocardial contractility index, stroke volume index, and cardiac output index. During dobutamine infusion, cardiac output index and stroke volume index were significantly reduced following cSCI compared to LAM. Overall, these stress testing results suggest that preclinical cervical SCI in rats can lead to, and therefore model, clinically relevant impairments in cardiopulmonary exercise performance, muscle endurance, and cardiovascular function.
心血管功能障碍在颈脊髓损伤(SCI)后对发病率和死亡率有显著影响。不幸的是,用于研究颈脊髓损伤后心血管功能障碍的临床前模型数量有限。此外,在生理应激测试期间,颈脊髓损伤对有氧能力和肌肉耐力的更广泛影响在临床前研究中也仍未得到充分研究。因此,在本研究中,我们使用一系列应激测试评估了颈脊髓损伤大鼠模型中多个生理系统的潜在缺陷。雌性Sprague-Dawley大鼠(n = 20)接受C8中线挫伤(cSCI)或仅行椎板切除术作为对照(LAM)。使用代谢跑步机进行运动应激测试以评估心肺适应性和恢复情况,或使用等长拉力任务评估前肢适应性。还进行了直立位应激测试和药物应激测试,以更直接地挑战心血管系统。我们的研究结果表明,cSCI大鼠的有氧适应性下降,运动后过量耗氧量失调证明了这一点。与LAM相比,cSCI大鼠的肌肉耐力也受损。在直立位应激测试期间,70%的cSCI大鼠收缩压下降约25 mmHg,舒张压下降20 mmHg,此外心率、心肌收缩力指数、每搏输出量指数和心输出量指数也有适度但显著的下降。在多巴酚丁胺输注期间,与LAM相比,cSCI后心输出量指数和每搏输出量指数显著降低。总体而言,这些应激测试结果表明,大鼠临床前颈脊髓损伤可导致并因此模拟心肺运动表现、肌肉耐力和心血管功能方面与临床相关的损伤。