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

Key points Using a wide array of experimental approaches, we demonstrate for the first time that spinal cord injury is associated with a rapid and sustained impairment in cardiac structure and function that is present as early as 1week post-injury. We provide novel data demonstrating that spinal cord injury elicits an altered Starling curve and myocardial fibrosis. The latter of these may be secondary to an up-regulation of transforming growth factor beta-1 and mothers against decapentaplegic homolog 3 mRNA, both of which form part of a well-known fibrotic signalling pathway. Passive hind-limb cycling averts the spinal cord injury-induced impairments in cardiac structure and function, prevents myocardial fibrosis and improves blood lipid profiles. Passive lower-limb cycling represents an elegant, cost-effective and widely accessible therapeutic strategy that may reduce the clinical cardiovascular burden imposed by spinal cord injury and other neurological disorders. 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; 2x30minday(-1), 5daysweek(-1) for 4weeks beginning 6days 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 (TGF beta(1)) 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. TGF beta(1) 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.