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1.
Am J Physiol Heart Circ Physiol ; 321(4): H716-H727, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34448635

RESUMO

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.


Assuntos
Circulação Cerebrovascular , Hemodinâmica , Hipotensão Ortostática/fisiopatologia , Artéria Cerebral Média/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Medula Espinal/fisiopatologia , Função Ventricular Esquerda , Adaptação Fisiológica , Animais , Modelos Animais de Doenças , Hipotensão Ortostática/etiologia , Pressão Negativa da Região Corporal Inferior , Masculino , Ratos Wistar , Traumatismos da Medula Espinal/complicações , Vértebras Torácicas , Fatores de Tempo
2.
J Neurooncol ; 132(1): 155-162, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28102486

RESUMO

While 2/3 of patients with ATRT are less than 3 years at diagnosis, the literature suggests younger children present with more aggressive disease and poorer outcome. However, little data exist on characteristics and outcome of patients diagnosed with ATRT in the first year of life. In particular, it is unclear whether they access similar treatments as do older children. We compared the cohort of patients ≤12 months from the Canadian ATRT registry to all cases extracted from the literature reported between 1996 and 2014 to describe their clinical and treatment characteristics, and potential prognostic factors. Twenty-six (33.7%) patients from the Canadian registry were ≤12 months at diagnosis as were 120 cases identified in the literature. Post-operatively, 46% of the registry's patients underwent palliation as opposed to 10.8% in the literature cohort. Palliative patients were significantly younger than those who received active therapy (3.3 vs. 6.6 months). While the use of high-dose chemotherapy (HDC) was relatively similar in both cohorts (42.9 and 35.5% respectively), radiotherapy (RT) use was significantly lower in the Canadian cohort (14.3 vs 44.9%). Children ≤6 months, who received active therapy, had a worst outcome than older ones. Gross total resection, HDC and adjuvant RT were associated with better outcomes. Eighty percent of the tested patients had evidence of germline mutation of INI1. While 1/3 of ATRT occurs within the first year of life, a large proportion only received palliative therapy. Even when actively treated, children ≤6 months fare worse. Some selected patients benefit from HDC.


Assuntos
Tumor Rabdoide/epidemiologia , Teratoma/epidemiologia , Canadá , Feminino , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Cuidados Paliativos/estatística & dados numéricos , Radioterapia Adjuvante , Sistema de Registros , Tumor Rabdoide/radioterapia , Tumor Rabdoide/cirurgia , Teratoma/radioterapia , Teratoma/cirurgia , Resultado do Tratamento
3.
Nat Commun ; 13(1): 1382, 2022 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-35296681

RESUMO

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.


Assuntos
Traumatismos da Medula Espinal , Animais , Coração , Estudos Prospectivos , Ratos , Medula Espinal , Traumatismos da Medula Espinal/complicações , Sistema Nervoso Simpático , Função Ventricular Esquerda
4.
J Neurotrauma ; 36(6): 950-961, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-29877162

RESUMO

Spinal cord injury (SCI) causes autonomic dysfunction, altered neurohumoral control, profound hemodynamic changes, and an increased risk of heart disease. In this prospective study, we investigated the cardiac consequences of chronic experimental SCI in rats by combining cutting edge in vivo techniques (magnetic resonance imaging [MRI] and left-ventricular [LV] pressure-volume catheterization) with histological and molecular assessments. Twelve weeks post-SCI, MRI-derived structural indices and in vivo LV catheterization-derived functional indices indicated the presence of LV atrophy (LV mass in Control vs. SCI = 525 ± 38.8 vs. 413 ± 28.6 mg, respectively; p = 0.0009), reduced ventricular volumes (left-ventricular end-diastolic volume in Control vs. SCI = 364 ± 44 vs. 221 ± 35 µL, respectively; p = 0.0004), and contractile dysfunction (end-systolic pressure-volume relationship in Control vs. SCI = 1.31 ± 0.31 vs. 0.76 ± 0.11 mm Hg/µL, respectively; p = 0.0045). Cardiac atrophy and contractile dysfunction in SCI were accompanied by significantly lower blood pressure, reduced circulatory norepinephrine, and increased angiotensin II. At the cellular level, we found the presence of reduced cardiomyocyte size and increased expression of angiotensin II type 1 receptors and transforming growth factor-beta receptors (TGF-ß receptor 1 and 2) post-SCI. Importantly, we found more than a two-fold increase in muscle ring finger-1 and Beclin-1 protein level following SCI, indicating the upregulation of the ubiquitin-proteasome system and autophagy-lysosomal machinery. Our data provide novel evidence that SCI-induced cardiomyocyte atrophy and systolic cardiac dysfunction are accompanied by an upregulation of proteolytic pathways, the activation of which is likely due to loss of trophic support from the sympathetic nervous system, neuromechanical unloading, and altered neurohumoral pathways.


Assuntos
Ventrículos do Coração/patologia , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/fisiopatologia , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia , Animais , Atrofia/etiologia , Modelos Animais de Doenças , Masculino , Proteólise , Ratos , Ratos Zucker , Regulação para Cima
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