Neuroprotective agents ineffective in mitigating autonomic dysreflexia following experimental spinal cord injury.

BACKGROUND AND OBJECTIVES: Loss of supraspinal cardiovascular control and secondary damage following spinal cord injury (SCI) lead to cardiovascular dysfunction, where autonomic dysreflexia (AD), triggered by stimuli below the injury, can cause uncontrolled blood pressure (BP) surges, posing severe health risks such as stroke and seizures. While anti-inflammatory neuroprotective agents have been studied for motor recovery, their impact on cardiovascular function remains under investigated. The objective was to assess the efficacy of four clinically approved neuroprotective agents in promoting cardiovascular recovery following SCI. METHODS: Male Wistar rats received contusion at the third thoracic spinal segment (T3). Fluoxetine, Glyburide, Valproic acid, and Indomethacin were first administered at 1 h or 6 h post-SCI, and every 12 h for two weeks thereafter. Four weeks following SCI, hemodynamics were measured at rest and during colorectal distension. Locomotor function was assessed prior to SCI and weekly for four weeks after SCI, using the Basso-Beattie-Bresnahan (BBB) locomotor scale. Quantitative comparisons of lesion area were performed. RESULTS: Contrary to the published literature, Indomethacin and Valproic acid resulted in high morbidity and mortality rates 60 % and 40 % respectively) within 2-3 days of administration. Fluoxetine, and Glyburide were well-tolerated. There were no differences in change in systolic BP with colorectal distension compared to control i.e., all experimental groups experienced severe episodes of AD [F(6, 67) = 0.94, p = 0.47]. There was no significant difference in BBB scores in any experimental group compared to control [F(18, 252) = 0.3, p = 0.99]. No between-group differences were observed in tissue sparing at the lesion epicentre [F(6, 422) = 6.98, p = 0.29]. DISCUSSION: Despite promising beneficial effect reported in previous studies, none of the drugs demonstrated improvement in cardiovascular or motor function. Indomethacin and Valproic acid exhibited unexpected high mortality at doses deemed safe in the literature. This emphasizes the necessity for reproducibility studies in pre-clinical research and underscores the importance of publishing null findings to guide future investigations.

Advancements in the neurocirculatory reflex response to hypoxia.

Hypoxia is a pivotal factor in the pathophysiology of various clinical conditions, including obstructive sleep apnea, which has a strong association with cardiovascular diseases like hypertension, posing significant health risks. Although the precise mechanisms linking hypoxemia-associated clinical conditions with hypertension remains incompletely understood, compelling evidence suggests that hypoxia induces plasticity of the neurocirculatory control system. Despite variations in experimental designs and the severity, frequency, and duration of hypoxia exposure, evidence from animal and human models consistently demonstrates the robust effects of hypoxemia in triggering reflex-mediated sympathetic activation. Both acute and chronic hypoxia alters neurocirculatory regulation and, in some circumstances, leads to sympathetic outflow and elevated blood pressures that persist beyond the hypoxic stimulus. Dysregulation of autonomic control could lead to adverse cardiovascular outcomes and increase the risk of developing hypertension.

The left ventricle increases contractility in response to baroreceptor unloading, which is sympathetically mediated in the anesthetized rat.

Contemporary discussion of the baroreflex includes the efferent vascular-sympathetic and cardiovagal arms. Since sympathetic postganglionic neurons also innervate the left ventricle (LV), it is often assumed that the LV produces a sympathetically mediated increase in contractility during baroreceptor unloading, but this has not been characterized using a load-independent index of contractility. We aimed to determine 1) whether LV contractility increases in response to baroreceptor unloading and 2) whether such increases are mediated via the sympathetic or parasympathetic arm of the autonomic nervous system. Ten male Wistar rats were anesthetized (urethane) and instrumented with arterial and LV pressure-volume catheters to measure mean arterial pressure (MAP) and load-independent LV contractility [maximal rate of increase in pressure adjusted to end-diastolic volume (PAdP/dtmax)], respectively. Rats were placed in a servo-controlled lower-body negative pressure (LBNP) chamber to reduce MAP by 10% for 60 s to mechanically unload baroreceptors under control conditions. LBNP was repeated in each animal following infusions of cardiac autonomic blockers using esmolol (sympathetic), atropine (parasympathetic), and esmolol + atropine. Under control conditions, PAdP/dtmax increased during baroreceptor unloading (26 ± 6 vs. 31 ± 9 mmHg·s-1·µL-1, P = 0.031). During esmolol, there was no increase in LV contractility during baroreceptor unloading (11 ± 2 vs. 12 ± 2, P = 0.125); however, during atropine, there was an increase in LV contractility during baroreceptor unloading (26 ± 6 vs. 31 ± 9, P = 0.019). During combined esmolol and atropine, there was a small increase in contractility versus control (13 ± 3 vs. 15 ± 4, P = 0.046). Our results demonstrate that, in anesthetized rats, LV contractility increases in response to baroreceptor unloading, which is largely sympathetically mediated.NEW & NOTEWORTHY This study empirically demonstrates a sympathetically mediated increase in LV contractility in response to baroreceptor unloading using a load-independent index of cardiac contractility in the anesthetized rat.

Transforming research systems for meaningful engagement: a reflexive thematic analysis of spinal cord injury researchers' barriers and facilitators to using the integrated knowledge translation guiding principles.

PURPOSE: To develop an in-depth understanding of spinal cord injury (SCI) researchers' barriers and facilitators to deciding to use 1) a partnered approach to research and, 2) systematically developed principles for guiding Integrated Knowledge Translation (IKT) in spinal cord injury research (IKT Guiding Principles). METHODS: Qualitative interview study with North American SCI researchers who were interested in using a partnered research approach. The research was conducted using an IKT approach, and interview data were analyzed using reflexive thematic analysis. RESULTS: Thirteen SCI researchers whose research focused on prevention, clinical, rehabilitation, and/or community SCI research were interviewed. Three themes were co-constructed with partners: 1) the principles are necessary but not sufficient for the implementation of a partnered approach to research; 2) relational capacity building is needed; and 3) institutional transformation is needed to value, resource, and support meaningful engagement. CONCLUSIONS: Supporting change that enables SCI researchers to adopt and implement the IKT Guiding Principles will require transformation at the individual (theme 1), relational (theme 2), and institutional levels (theme 3). Findings provide clear, practical, and tangible actions to promote change that can support meaningful engagement in the SCI Research System.

Providing researchers with clear, procedural information and strategies to use each of the Integrated Knowledge Translation Guiding Principles in practice can support the implementation of the principles and partnered research in rehabilitation-based research.Fostering and evaluating resources and initiatives that help researchers network, build connections, and receive mentorship could help spinal cord injury researchers partner more effectively.Academic, research, and funding systems must ensure their practices, structures, culture, and processes enable, value, resource, support, and/or incentivize partnered research to ensure the research being conducted is relevant and useful in addressing the needs and priorities of research users.

Supporting meaningful research partnerships: an interview study applying behavior change theory to develop relevant recommendations for researchers.

Research partnerships, while promising for ensuring translation of relevant and useable findings, are challenging and need support. This study aimed to apply behavior change theory to understand and support researchers' adoption of a research partnership approach and the Integrated Knowledge Translation (IKT) Guiding Principles for conducting and disseminating spinal cord injury (SCI) research in partnership. Using an IKT approach, SCI researchers across Canada and the USA completed a survey (n = 22) and were interviewed (n = 13) to discuss barriers and facilitators to deciding to partner and follow the IKT Guiding Principles. The Behaviour Change Wheel, Theoretical Domains Framework (TDF), and Mode of Delivery Ontology were used to develop the survey, interview questions, and guided analyses of interview data. COM-B and TDF factors were examined using descriptive statistics and abductive analyses of barriers and facilitators of decisions to partner and/or use the IKT Guiding Principles. TDF domains from the interview transcripts were then used to identify intervention, content, and implementation options. 142 factors (79 barriers, 63 facilitators) related to deciding to partner, and 292 factors (187 barriers, 105 facilitators) related to deciding to follow the IKT Guiding Principles were identified. Barriers to partnering or use the IKT Guiding Principles were primarily related to capability and opportunity and relevant intervention options were recommended. Interventions must support researchers in understanding how to partner and use the IKT Guiding Principles while navigating a research system, which is not always supportive of the necessary time and costs required for meaningful research partnerships.

Research partnerships, which expand beyond researchers solely working with other researchers, are said to be promising for helping to move research into practice. However, there is a lack in understanding of how to support meaningful research partnerships with those who are not part of academia. This study interviewed spinal cord injury researchers to understand what helps and prevents them from deciding to partner when conducting research projects. Results suggest that researchers do not lack motivation to partner; however, their ability and opportunity to do so is lacking. Overall, support is needed to help researchers understand how to work in partnership within the research system.

Sex differences in heart disease prevalence among individuals with spinal cord injury: A population-based study.

CONTEXT/OBJECTIVE: The risk for cardiovascular disease is amplified following spinal cord injury, but whether risk differs between the sexes remains unknown. Here, we evaluated sex differences in the prevalence of heart disease among individuals with spinal cord injury, and compared sex differences with able-bodied individuals. DESIGN: The design was a cross-sectional study. Multivariable logistic regression analysis was conducted, using inverse probability weighting to account for the sampling method and to adjust for confounders. SETTING: Canada. PARTICIPANTS: Individuals who participated in the national Canadian Community Health Survey. INTERVENTIONS: Not applicable. OUTCOME MEASURES: Self-reported heart disease. RESULTS: Among 354 individuals with spinal cord injury, the weighted prevalence of self-reported heart disease was 22.9% in males and 8.7% in females, with an inverse-probability weighted odds ratio of 3.44 (95% CI 1.70-6.95) for males versus females. Among 60,605 able-bodied individuals, the prevalence of self-reported heart disease was 5.8% in males and 4.0% in females, with an inverse probability weighted odds ratio of 1.62 (95% CI 1.50-1.75) for males versus females. The effect of male sex on increasing heart disease prevalence was about two times higher among individuals with spinal cord injury than able-bodied individuals (relative difference in inverse probability weighted odds ratios = 2.12, 95% CI 1.08-4.51). CONCLUSION: Males with spinal cord injury exhibit a significantly higher prevalence of heart disease, compared with females with spinal cord injury. Moreover, relative to able-bodied individuals, spinal cord injury amplifies sex-related differences in heart disease. Overall, this work will inform targeted cardiovascular prevention strategies, and may also inform a better understanding of cardiovascular disease progression in both able-bodied and individuals with spinal cord injury.

A cross-species validation of single-beat metrics of cardiac contractility.

The assessment of left ventricular (LV) contractility in animal models is useful in various experimental paradigms, yet obtaining such measures is inherently challenging and surgically invasive. In a cross-species study using small and large animals, we comprehensively tested the agreement and validity of multiple single-beat surrogate metrics of LV contractility against the field-standard metrics derived from inferior vena cava occlusion (IVCO). Fifty-six rats, 27 minipigs and 11 conscious dogs underwent LV and arterial catheterization and were assessed for a range of single-beat metrics of LV contractility. All single-beat metrics were tested for the various underlying assumptions required to be considered a valid metric of cardiac contractility, including load-independency, sensitivity to inotropic stimulation, and ability to diagnose contractile dysfunction in cardiac disease. Of all examined single-beat metrics, only LV maximal pressure normalized to end-diastolic volume (EDV), end-systolic pressure normalized to EDV, and the maximal rate of rise of the LV pressure normalized to EDV showed a moderate-to-excellent agreement with their IVCO-derived reference measure and met all the underlying assumptions required to be considered as a valid cardiac contractile metric in both rodents and large-animal models. Our findings demonstrate that single-beat metrics can be used as a valid, reliable method to quantify cardiac contractile function in basic/preclinical experiments utilizing small- and large-animal models KEY POINTS: Validating and comparing indices of cardiac contractility that avoid caval occlusion would offer considerable advantages for the field of cardiovascular physiology. We comprehensively test the underlying assumptions of multiple single-beat indices of cardiac contractility in rodents and translate these findings to pigs and conscious dogs. We show that when performing caval occlusion is unfeasible, single-beat metrics can be utilized to accurately quantify cardiac inotropic function in basic and preclinical research employing various small and large animal species. We report that maximal left-ventricular (LV)-pressure normalized to end-diastolic volume (EDV), LV end-systolic pressure normalized to EDV and the maximal rate of rise of the LV pressure waveform normalized to EDV are the best three single-beat metrics to measure cardiac inotropic function in both small- and large-animal models.

Temporal Changes of Cardiac Structure, Function, and Mechanics During Sub-acute Cervical and Thoracolumbar Spinal Cord Injury in Humans: A Case-Series.

Individuals with cervical spinal cord injury (SCI) experience deleterious changes in cardiac structure and function. However, knowledge on when cardiac alterations occur and whether this is dependent upon neurological level of injury remains to be determined. Transthoracic echocardiography was used to assess left ventricular structure, function, and mechanics in 10 male individuals (median age 34 years, lower and upper quartiles 32-50) with cervical (n = 5, c-SCI) or thoracolumbar (n = 5, tl-SCI) motor-complete SCI at 3- and 6-months post-injury. Compared to the 3-month assessment, individuals with c-SCI displayed structural, functional, and mechanical changes during the 6-month assessment, including significant reductions in end diastolic volume [121 mL (104-139) vs. 101 mL (99-133), P = 0.043], stroke volume [75 mL (61-85) vs. 60 mL (58-80), P = 0.042], myocardial contractile velocity (S') [0.11 m/s (0.10-0.13) vs. 0.09 m/s (0.08-0.10), P = 0.043], and peak diastolic longitudinal strain rate [1.29°/s (1.23-1.34) vs. 1.07°/s (0.95-1.15), P = 0.043], and increased early diastolic filling over early myocardial relaxation velocity (E/E') ratio [5.64 (4.71-7.72) vs. 7.48 (6.42-8.42), P = 0.043]. These indices did not significantly change in individuals with tl-SCI between time points. Ejection fraction was different between individuals with c-SCI and tl-SCI at 3 [61% (57-63) vs. 54% (52-55), P < 0.01] and 6 months [58% (57-62) vs. 55% (52-56), P < 0.01], though values were considered normal. These results demonstrate that individuals with c-SCI exhibit significant reductions in cardiac function from 3 to 6 months post-injury, whereas individuals with tl-SCI do not, suggesting the need for early rehabilitation to minimize cardiac consequences in this specific population.

Sulfaphenazole reduces thermal and pressure injury severity through rapid restoration of tissue perfusion.

Pressure injuries, also known as pressure ulcers, are regions of localized damage to the skin and/or underlying tissue. Repeated rounds of ischemia-reperfusion (I/R) have a major causative role for tissue damage in pressure injury. Ischemia prevents oxygen/nutrient supply, and restoration of blood flow induces a burst of reactive oxygen species that damages blood vessels, surrounding tissues and can halt blood flow return. Minimizing the consequences of repeated I/R is expected to provide a protective effect against pressure injury. Sulfaphenazole (SP), an off patent sulfonamide antibiotic, is a potent CYP 2C6 and CYP 2C9 inhibitor, functioning to decrease post-ischemic vascular dysfunction and increase blood flow. The therapeutic effect of SP on pressure injury was therefore investigated in apolipoprotein E knockout mice, a model of aging susceptible to ischemic injury, which were subjected to repeated rounds of I/R-induced skin injury. SP reduced overall severity, improved wound closure and increased wound tensile strength compared to vehicle-treated controls. Saliently, SP restored tissue perfusion in and around the wound rapidly to pre-injury levels, decreased tissue hypoxia, and reduced both inflammation and fibrosis. SP also demonstrated bactericidal activity through enhanced M1 macrophage activity. The efficacy of SP in reducing thermal injury severity was also demonstrated. SP is therefore a potential therapeutic option for pressure injury and other ischemic skin injuries.

Influence of respiratory loading on left-ventricular function in cervical spinal cord injury.

Cervical spinal cord injury (C-SCI) negatively impacts cardiac and respiratory function. As the heart and lungs are linked via the pulmonary circuit these systems are interdependent. Here, we utilized inspiratory and expiratory loading to assess whether augmenting the respiratory pump improves left-ventricular (LV) filling and output in individuals with motor-complete C-SCI. We hypothesized LV end-diastolic volume (LVEDV) would increase and decrease with inspiratory and expiratory loading, respectively. Participants (C-SCI: 7M/1F, 35 ± 7 years; able-bodied: 7M/1F, 32 ± 6 years) were assessed under five conditions during 45° head-up tilt; unloaded, inspiratory loading with -10 and -20 cmH2 O oesophageal pressure (Poes ) on inspiration, and expiratory loading with +10 and +20 cmH2 O Poes on expiration. An oesophageal balloon catheter monitored Poes , and LV structure and function were assessed by echocardiography. In C-SCI only, (1) +20 cmH2 O reduced LVEDV vs. unloaded (81 ± 15 vs. 88 ± 11 ml, P = 0.006); (2) heart rate was higher during +20 cmH2 O compared to unloaded (P = 0.001) and +10 cmH2 O (P = 0.002); (3) cardiac output was higher during +20 cmH2 O than unloaded (P = 0.002); and (4) end-expiratory lung volume was higher during +20 cmH2 O vs. unloaded (63 ± 10 vs. 55 ± 13% total lung capacity, P = 0.003) but was unaffected by inspiratory loading. In both groups, -10 and -20 cmH2 O had no significant effect on LVEDV. These findings suggest greater expiratory positive pressure acutely impairs LV filling in C-SCI, potentially via impaired venous return, mediastinal constraint and/or direct ventricular interaction subsequent to dynamic hyperinflation. Inspiratory loading did not significantly improve LV function in C-SCI and neither inspiratory nor expiratory loading affected cardiac function or lung volumes in able-bodied participants. KEY POINTS: Cervical spinal cord injury (C-SCI) alters both the cardiac and the respiratory system, but little is known about how these systems interact following injury. Here, we manipulated inspiratory or expiratory intrathoracic pressure (ITP) to mechanistically test the role of the respiratory pump in circulatory function in highly trained individuals with C-SCI and an able-bodied reference group. In individuals with C-SCI, greater ITP during expiratory loading caused dynamic hyperinflation that was associated with impaired left-ventricular filling. More negative ITP during inspiratory loading did not significantly alter left-ventricular volumes in either group. Interventions that prevent dynamic hyperinflation and/or enhance the ability to generate expiratory pressures may help preserve left-ventricular filling in individuals with C-SCI.

Spinal cord injury impairs cardiac function due to impaired bulbospinal sympathetic control.

Spinal cord injury chronically alters cardiac structure and function and is associated with increased odds for cardiovascular disease. Here, we investigate the cardiac consequences of spinal cord injury on the acute-to-chronic continuum, and the contribution of altered bulbospinal sympathetic control to the decline in cardiac function following spinal cord injury. By combining experimental rat models of spinal cord injury with prospective clinical studies, we demonstrate that spinal cord injury causes a rapid and sustained reduction in left ventricular contractile function that precedes structural changes. In rodents, we experimentally demonstrate that this decline in left ventricular contractile function following spinal cord injury is underpinned by interrupted bulbospinal sympathetic control. In humans, we find that activation of the sympathetic circuitry below the level of spinal cord injury causes an immediate increase in systolic function. Our findings highlight the importance for early interventions to mitigate the cardiac functional decline following spinal cord injury.

Hemorrhage and Locomotor Deficits Induced by Pain Input after Spinal Cord Injury Are Partially Mediated by Changes in Hemodynamics.

Nociceptive input diminishes recovery and increases lesion area after a spinal cord injury (SCI). Recent work has linked these effects to the expansion of hemorrhage at the site of injury. The current article examines whether these adverse effects are linked to a pain-induced rise in blood pressure (BP) and/or flow. Male rats with a low-thoracic SCI were treated with noxious input (electrical stimulation [shock] or capsaicin) soon after injury. Locomotor recovery and BP were assessed throughout. Tissues were collected 3 h, 24 h, or 21 days later. Both electrical stimulation and capsaicin undermined locomotor function and increased the area of hemorrhage. Changes in BP/flow varied depending on type of noxious input, with only shock producing changes in BP. Providing behavioral control over the termination of noxious stimulation attenuated the rise in BP and hemorrhage. Pretreatment with the α-1 adrenergic receptor inverse agonist, prazosin, reduced the stimulation-induced rise in BP and hemorrhage. Prazosin also attenuated the adverse effect that noxious stimulation has on long-term recovery. Administration of the adrenergic agonist, norepinephrine 1 day after injury induced an increase in BP and disrupted locomotor function, but had little effect on hemorrhage. Further, inducing a rise in BP/flow using norepinephrine undermined long-term recovery and increased tissue loss. Mediational analyses suggest that the pain-induced rise in blood flow may foster hemorrhage after SCI. Increased BP appears to act through an independent process to adversely affect locomotor performance, tissue sparing, and long-term recovery.

Development of a Spinal Cord Injury Model Permissive to Study the Cardiovascular Effects of Rehabilitation Approaches Designed to Induce Neuroplasticity.

As primary medical care for spinal cord injury (SCI) has improved over the last decades there are more individuals living with neurologically incomplete (vs. complete) cervical injuries. For these individuals, a number of promising therapies are being actively researched in pre-clinical settings that seek to strengthen the remaining spinal pathways with a view to improve motor function. To date, few, if any, of these interventions have been tested for their effectiveness to improve autonomic and cardiovascular (CV) function. As a first step to testing such therapies, we aimed to develop a model that has sufficient sparing of descending sympathetic pathways for these interventions to target yet induces robust CV impairment. Twenty-six Wistar rats were assigned to SCI (n = 13) or naïve (n = 13) groups. Animals were injured at the T3 spinal segment with 300 kdyn of force. Fourteen days post-SCI, left ventricular (LV) and arterial catheterization was performed to assess in vivo cardiac and hemodynamic function. Spinal cord lesion characteristics along with sparing in catecholaminergic and serotonergic projections were determined via immunohistochemistry. SCI produced a decrease in mean arterial pressure of 17 ± 3 mmHg (p < 0.001) and left ventricular contractility (end-systolic elastance) of 0.7 ± 0.1 mmHg/µL (p < 0.001). Our novel SCI model produced significant decreases in cardiac and hemodynamic function while preserving 33 ± 9% of white matter at the injury epicenter, which we believe makes it a useful pre-clinical model of SCI to study rehabilitation approaches designed to induce neuroplasticity.

Effects of early exercise training on the severity of autonomic dysreflexia following incomplete spinal cord injury in rodents.

Hemodynamic instability and cardiovascular (CV) dysfunction are hallmarks of patients living with cervical and high thoracic spinal cord injuries (SCI). Individuals experience bouts of autonomic dysreflexia (AD) and persistent hypotension which hamper the activities of daily living. Despite the widespread use of exercise training to improve health and CV function after SCI, little is known about how different training modalities impact hemodynamic stability and severity of AD in a model of incomplete SCI. In this study, we used implantable telemetry devices to assess animals with T2 contusions following 3.5 weeks of exercise training initiated 8 days post-injury: passive hindlimb cycling (T2-CYC, n = 5) or active forelimb swimming (T2-SW, n = 6). Uninjured and non-exercised SCI control groups were also included (CON, n = 6; T2-CON, n = 7; T10-CON, n = 6). Five weeks post-injury, both T2-CON and T2-CYC presented with resting hypotension compared to uninjured CON and T10-CON groups; no differences were noted in resting blood pressure in T2-SW versus CON and T10-CON. Furthermore, pressor responses to colorectal distention (AD) were larger in all T2-injured groups compared to T10-CON, and were not attenuated by either form of exercise training. Interestingly, when T2-injured animals were re-stratified based on terminal BBB scores (regardless of training group), animals with limited hindlimb recovery (T2-LOW, n = 7) had more severe AD responses. Our results suggest that the spontaneous recovery of locomotor and autonomic function after severe but incomplete T2 SCI also influences the severity of AD, and that short periods (3.5 weeks) of passive hindlimb cycling or active forelimb swimming are ineffective in this model.

Markers of susceptibility to cardiac arrhythmia in experimental spinal cord injury and the impact of sympathetic stimulation and exercise training.

Injury to descending autonomic (sympathetic) pathways is common after high-level spinal cord injury (SCI) and associated with abnormal blood pressure and heart rate regulation. In individuals with high-level SCI, abnormal sympathovagal balance (such as during autonomic dysreflexia; paroxysmal hypertension provoked by sensory stimuli below the injury) is proarrhythmogenic. Exercise training is a key component of SCI rehabilitation and management of cardiovascular disease risk, but it is unclear whether exercise training influences susceptibility to cardiac arrhythmia. We aimed to evaluate: (i) whether susceptibility to arrhythmia increases in a rodent-model of SCI; (ii) the impact of the sympathomimetic drug dobutamine (DOB) on arrhythmia risk; (iii) whether exercise training ameliorates arrhythmia risk. Twenty-one Wistar rats were divided into 3 subgroups: T2-contusive SCI (T2, n = 7), T2-contusive SCI completing passive hindlimb cycling training (PHLC, n = 7), and T10-contusive SCI (T10, n = 7). Known electrocardiographic arrhythmia markers and heart rate variability parameters were evaluated before (PRE), 1-week (POST) and 5-weeks post-SCI (TERM) at baseline and during DOB infusion (30 µg/kg/min). Baseline markers of arrhythmia risk were increased in both T2 and T10 animals. DOB decreased R-R interval (p < 0.001), and increased markers of risk for ventricular arrhythmia, particularly in high-level (T2) animals (p < 0.05). Exercise training blunted the exacerbation of markers of arrhythmia risk in the presence of DOB. Markers of risk for cardiac arrhythmia are increased in experimental SCI, and DOB further increases arrhythmia risk in high-level SCI. Exercise training did not improve markers of arrhythmia risk at rest, but did ameliorate markers of arrhythmia risk during sympathetic stimulation.

Experimental high thoracic spinal cord injury impairs the cardiac and cerebrovascular response to orthostatic challenge in rats.

Spinal cord injury (SCI) impairs the cardiovascular responses to postural challenge, leading to the development of orthostatic hypotension (OH). Here, we apply lower body negative pressure (LBNP) to rodents with high-level SCI to demonstrate the usefulness of LBNP as a model for experimental OH studies, and to explore the effect of simulated OH on cardiovascular and cerebrovascular function following SCI. Male Wistar rats (n = 34) were subjected to a sham or T3-SCI surgery and survived into the chronic period postinjury (i.e., 8 wk). Cardiac function was tracked via ultrasound pre- to post-SCI to demonstrate the clinical utility of our model. At study termination, we conducted left-ventricular (LV) catheterization and insonated the middle cerebral artery to investigate the hemodynamic, cardiac, and cerebrovascular response to a mild dose of LBNP that is sufficient to mimic clinically defined OH in rats with T3-SCI but not sham animals. In response to mimicked OH, there was a greater decline in stroke volume, cardiac output, maximal LV pressure, and blood pressure in SCI compared with sham (P < 0.034), whereas heart rate was increased in sham but decreased in SCI (P < 0.029). SCI animals also had an exaggerated reduction in peak, minimum and mean middle cerebral artery flow, for a given change in blood pressure, in response to LBNP (P < 0.033), implying impaired dynamic cerebral autoregulation. Using a preclinical SCI model of OH, we demonstrate that complete high thoracic SCI impairs the cardiac response to OH and disrupts dynamic cerebral autoregulation.NEW & NOTEWORTHY This is the first use of LBNP to interrogate the cardiac and cerebrovascular responses to simulated OH in a preclinical study of SCI. Here, we demonstrate the utility of our simulated OH model and use it to demonstrate that SCI impairs the cardiac response to simulated OH and disrupts dynamic cerebrovascular autoregulation.

Weight-Based Aspirin Dosing May Further Reduce the Incidence of Venous Thromboembolism Following Primary Total Joint Arthroplasty.

BACKGROUND: Obesity poses a challenge to thromboembolic prophylaxis following total joint arthroplasty (TJA). The purpose of this study is to evaluate a weight-based aspirin dosing regimen for prevention of venous thromboembolism (VTE) following TJA. METHODS: This is a retrospective observational study of 2403 patients who underwent primary total hip or knee arthroplasty at one institution. A weight-based aspirin dosing regimen for VTE prophylaxis was administered to 1247 patients: patients weighing ≥120 kg received 325 mg aspirin twice daily (BID) and those weighing <120 kg received 81 mg aspirin BID for 4 weeks. In total, 1156 patients in the comparison cohort received 81 mg aspirin BID. VTE and gastrointestinal bleeding events were identified through chart review at 42 days and 6 months postoperatively. A multivariable logistic regression was performed to adjust for covariates. RESULTS: The weight-based aspirin cohort had a significantly lesser incidence of VTE at 42 days (P = .03, relative risk [RR] 0.31, 95% confidence interval 0.12-0.82) and 6 months (P = .03, RR 0.38, 95% confidence interval 0.18-0.80). There was no difference in VTE incidence between total hip arthroplasty and total knee arthroplasty cases (P = .8). There was no difference in gastrointestinal bleeding events between the cohorts at 42 days (P = .69) or 6 months (P = .92). Subanalysis of patients weighing ≥120 kg demonstrated a significant difference between the cohorts with a VTE incidence of 3.48% and 0% in the 81 mg and weight-based cohorts, respectively (P = .02). CONCLUSION: Patients prescribed a weight-based aspirin regimen had significantly fewer VTEs after TJA compared to historical controls with an RR reduction of 69% at 6 weeks and 62% at 6 months postoperatively. This suggests the need to factor patient weight when determining postoperative VTE prophylaxis with aspirin.