Spinal Cord Injury Causes Systolic Dysfunction and Cardiomyocyte Atrophy

Abstract

Individuals with spinal cord injury (SCI) have been shown to exhibit systolic, and to a lesser extent, diastolic cardiac dysfunction. However, previous reports of cardiac dysfunction in this population are confounded by the changing loading conditions after SCI and as such, whether cardiac dysfunction per se is present is still unknown. Therefore, our aim was to establish if load-independent cardiac dysfunction is present after SCI, to understand the functional cardiac response to SCI, and to explore the changes within the cellular milieu of the myocardium. Here, we applied in vivo echocardiography and left-ventricular (LV) pressure-volume catheterization with dobutamine infusions to our Wistar rodent model of cardiac dysfunction 5 weeks following high (T2) thoracic contusion SCI, while also examining the morphological and transcriptional alterations of cardiomyocytes. We found that SCI significantly impairs systolic function independent of loading conditions (end-systolic elastance in control: 1.35 ± 0.15; SCI: 0.65 ± 0.19 mm Hg/μL). The reduction in contractile indices is accompanied by a reduction in width and length of cardiomyocytes as well as alterations in the LV extracellular matrix. Importantly, we demonstrate that the reduction in the rate (dP/dtmax) of LV pressure rise can be offset with beta-adrenergic stimulation, thereby experimentally implicating the loss of descending sympatho-excitatory control of the heart as a principle cause of LV dysfunction in SCI. Our data provide evidence that SCI induces systolic cardiac dysfunction independent of loading conditions and concomitant cardiomyocyte atrophy that may be underpinned by changes in the genes regulating the cardiac extracellular matrix.

Keywords: contractility; pressure-volume relationship; spinal cord injury; sympathetic nervous system; ventricular function.

Conflict of interest statement

No competing financial interests exist.

Figures

FIG. 1.

Overview of experimental design to determine how spinal cord injury (SCI) impacts cardiac function. Adult Wistar rats underwent echocardiography prior to injury to establish pre-injury parameters. Next, rats were given a severe spinal cord contusion (day 0). At 7 and 30 days post-SCI, each rat was assessed using echocardiography to determine structural and functional changes to the left ventricle (LV). At 31 days post-injury the LV was cannulated with a pressure-volume conductance catheter via a closed chest approach to assess in vivo load-independent cardiac contractile function. Following this, animals were sacrificed and their organs were harvested and processed in preparation for histology and molecular biology. Color image is available online at www.liebertpub.com/neu

FIG. 2.

Representative echocardiography images of uninjured control (CON) and spinal cord injury (SCI; panel a). Left-ventricular internal diameter during diastole (LVIDd; panel b), stroke volume (SV; panel c), and cardiac output (CO; panel d) were all significantly reduced following SCI compared with CON (p < 0.05; Table 1; n = 4). At study termination, the SCI rats exhibited lower systolic blood pressure (SBP; panel e; n = 5) and mean arterial pressure (MAP; panel f). We observed a significantly lower resting heart rate (HR; panel g) and low frequency SBP power (panel h) following SCI (p < 0.05). Data are displayed as mean ± standard error. ****p < 0.0001 CON vs. SCI; ***p < 0.001 CON vs. SCI; **p < 0.01 CON vs. SCI; *p < 0.05 CON vs. SCI. Color image is available online at www.liebertpub.com/neu

FIG. 3.

Pressure-volume derived indices in response to dobutamine infusions at increasing concentrations. Note the progressive increase in heart rate (HR; panel a) and dP/dtmax (panel d). Of note is the significant increase in dP/dtmax (panel d) after spinal cord injury (SCI). However, end-diastolic pressure (Ped) was persistently low in SCI despite increasing dobutamine concentrations (panel f). All outcomes demonstrated a significant interaction effect. N = 5. ****p < 0.0001 uninjured control (CON) vs. SCI; ***p < 0.001 CON vs. SCI; **p < 0.01 CON vs. SCI; *p < 0.05 CON vs. SCI. CO, cardiac output; SV, stroke volume. Color image is available online at www.liebertpub.com/neu

FIG. 4.

Representative pressure-volume loops obtained from 1 animal per group during inferior vena cava occlusions demonstrate the significant decrease in pressure and volume-generating capacity after spinal cord injury (SCI; panels a,b). Mixed model linear regression reveals significant decreases in all three measure of load-independent contractility including the end-systolic pressure (Pes) to volume (Ves) relationship (panel c), dP/dtmax-end diastolic volume (Ved) relationship (panel d), as well as pre-load recruitable stroke work (SW; panel e). We observed no change in the end-diastolic pressure (Ped) to volume relationship after SCI (panel f). N = 5. * = p < 0.05 uninjured control (CON) vs. SCI. Color image is available online at www.liebertpub.com/neu

FIG. 5.

Cardiomyocyte immunohistochemistry reveals a significant decrease in myocyte length, as well as a significant decrease in myocyte width after spinal cord injury (SCI; n = 4) compared with uninjured control (CON; n = 4). Arrows indicate connexin-labeled end plates and arrowheads indicate the z-disk boundaries. Histograms represent binned data at either every 1 μm (αA width) or every 10 μm (myocyte length), overlaid with a Gaussian curve. Scale bar = 10 μm. * = p < 0.05 CON vs. SCI. Color image is available online at www.liebertpub.com/neu

FIG. 6.

Neuroanatomical representation of the sympathetic-mediated pathophysiology leading to cardiac dysfunction after spinal cord injury (SCI). Under normal physiological conditions pre-ganglionic neurons within the thoracic and lumbar spinal cord are controlled by supraspinal brainstem centers (i.e., rostral ventrolateral medulla). To maintain cardiac function, direct sympathetic control to the heart itself, as well as control over major venous, arterial, and adrenergic systems (i.e., adrenal medulla) is critical. Here, we depict the decentralization of the sympathetic nervous system after T2 contusion SCI that ultimately leads to cardiac dysfunction and maladaptive remodeling. Schematic representations of pressure-volume (PV) loops for SCI (orange) are displayed, overlaid on a representation of a normal physiological response (blue). SCI resulted in significantly decreased pressure-generating capacity, which may be attributed to the significant decentralization of the heart itself and/or the adrenal medulla, leading to decreased circulating catecholamines and reduced beta stimulation to the left ventricle (i.e., “1. Loss of Pressure”). This hypothesis is further supported by the complete restoration of pressure-generating capacity with dobutamine, a beta agonist (Fig. 3). Further, SCI induced a loss of volume-generating capacity (i.e., “2. Loss of Volume”), which can be attributed to loss of control over the inferior vena cava, preventing optimal blood flow return to the right atrium (i.e., pre-load). The extent of injury spread depicted in this schematic is based on previous modeling of this experimental injury. Solid lines indicate intact sympathetic control. Dotted lines indicate partial sympathetic ganglionic control from remaining sympathetic pre-ganglionic neurons. Faded lines indicate decentralization of sympathetic pre-ganglionic neurons and thus improper control of ganglionic neurons. PV loops are depicted in the classical volume (x-axis) versus pressure (y-axis). CG, celiac ganglion; CNX, cranial nerve X (vagus nerve); IMG, inferior mesenteric ganglion; IVC, inferior vena cava; SG, stellate ganglion; SMG, superior mesenteric ganglion. Color image is available online at www.liebertpub.com/neu