Passive Hind-Limb Cycling Reduces the Severity of Autonomic Dysreflexia After Experimental Spinal Cord Injury.

BACKGROUND: Spinal cord injury (SCI) induces alterations in cardio-autonomic control of which autonomic dysreflexia (AD), a condition characterized by life-threatening hypertension, is arguably the most insidious. Passive hind-limb cycling represents a low-cost therapeutic intervention with demonstrable cardiovascular, sensory, and motor benefits. OBJECTIVE: To investigate the effect of passive hind-limb cycling on AD in rodents with T3 SCI. METHODS: Forty-five male Wistar rats were evenly assigned to either uninjured control (CON), SCI, or SCI plus hind-limb cycling exercise (SCI-EX). At the end of the experimental period (day 32), rats were randomly assigned to stream 1 (n = 24) or stream 2 (n = 21). Stream 1 rats were assessed for AD severity (pressor response to colorectal distension) and were then perfused for tissue dissection and immunohistochemistry. Stream 2 rats underwent excision of the superior mesenteric artery for in vitro myography assessments. RESULTS: From 2 weeks post-SCI onwards, SCI-EX rats exhibited a significant reduction in the pressor response to colorectal distension versus SCI (P< .001). Reduced AD severity in SCI-EX rats was accompanied by a prevention of the SCI-induced increase in density of CGRP(+)afferents in the dorsal horn (P= .001). Conversely, both SCI and SCI-EX rats exhibited a similar degree of mesenteric endothelial dysfunction and α-adrenoceptor hypersensitivity versus CON. CONCLUSION: Passive hind-limb cycling reduces the severity of AD in SCI, and is correlated with changes in primary afferent morphology, but has limited effects on the peripheral vasculature.

Characterizing the temporal development of cardiovascular dysfunction in response to spinal cord injury.

Spinal cord injury (SCI) is associated with rapid and sustained impairments in cardiovascular function that ultimately cause an early onset of cardiovascular disease. We know remarkably little about the temporal progression of cardiovascular disturbances, but such an understanding is critical to inform clinical management and develop appropriate intervention strategies. To characterize the cardiovascular response to SCI, six male Wistar rats were instrumented with telemetry and assessed for continuous arterial blood pressure (BP), core body temperature, and heart rate (HR) 7 days before and up to 28 days after T3 SCI. Hemodynamic variables were averaged day by day and hour by hour. Spontaneously occurring autonomic dysreflexia (AD) was characterized by applying a novel algorithm to continuous BP and HR data, and induced AD was assessed weekly via the BP response to colorectal distension. Systolic BP was reduced at all time points after SCI compared with before SCI (p<0.003), except at 4 and 6 days post-injury. Core body temperature was reduced at 2 days post-SCI only (p=0.001). The nocturnal dip in BP and temperature observed pre-SCI was absent during the first 14 days post-SCI, but returned from 21 days post-SCI on (p<0.024). The frequency and severity of spontaneously occurring AD events were significantly less between days 6 and 10 post-SCI compared all other time points (p<0.037). The pressor response to colorectal distension was greater at 14, 21, and 28 days post-SCI compared with at 7 days post-SCI (all p<0.004). In conclusion, SCI induces rapid and profound alterations in basal hemodynamics and diurnal rhythms that partially recover by 14 days post-SCI. AD, on the other hand, is acutely present post-SCI, but the frequency and severity of AD events increase substantially from 14 days post-SCI on.

Passive hind-limb cycling improves cardiac function and reduces cardiovascular disease risk in experimental spinal cord injury.

Spinal cord injury (SCI) causes altered autonomic control and severe physical deconditioning that converge to drive maladaptive cardiac remodelling. We used a clinically relevant experimental model to investigate the cardio-metabolic responses to SCI and to establish whether passive hind-limb cycling elicits a cardio-protective effect. Initially, 21 male Wistar rats were evenly assigned to three groups: uninjured control (CON), T3 complete SCI (SCI) or T3 complete SCI plus passive hind-limb cycling (SCI-EX; 2 × 30 min day(-1), 5 days week(-1) for 4 weeks beginning 6 days post-SCI). On day 32, cardio-metabolic function was assessed using in vivo echocardiography, ex vivo working heart assessments, cardiac histology/molecular biology and blood lipid profiles. Twelve additional rats (n = 6 SCI and n = 6 SCI-EX) underwent in vivo echocardiography and basal haemodynamic assessments pre-SCI and at days 7, 14 and 32 post-SCI to track temporal cardiovascular changes. Compared with CON, SCI exhibited a rapid and sustained reduction in left ventricular dimensions and function that ultimately manifested as reduced contractility, increased myocardial collagen deposition and an up-regulation of transforming growth factor beta-1 (TGFß1) and mothers against decapentaplegic homolog 3 (Smad3) mRNA. For SCI-EX, the initial reduction in left ventricular dimensions and function at day 7 post-SCI was completely reversed by day 32 post-SCI, and there were no differences in myocardial contractility between SCI-EX and CON. Collagen deposition was similar between SCI-EX and CON. TGFß1 and Smad3 were down-regulated in SCI-EX. Blood lipid profiles were improved in SCI-EX versus SCI. We provide compelling novel evidence that passive hind-limb cycling prevents cardiac dysfunction and reduces cardiovascular disease risk in experimental SCI.