Mechanisms of Arrhythmia Susceptibility in Spinal Cord Injured Rats

脊髓损伤大鼠心律失常易感性机制

• 批准号: 8094386
• 负责人: STEPHEN E DICARLO
• 金额: $ 58.61万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2014-02-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8094386
• 关键词: Acute; Address; Aerobic; Animals; Antibiotics; Antibodies; Area; Arrhythmia; Automatism; Autonomic Dysfunction; Bladder; Bladder Control; Ca(2+)-Transporting ATPase; Calcium; Caliber; Cardiac; Cardiovascular Diseases; Cardiovascular system; Caring; Cause of Death; Centers for Disease Control and Prevention (U.S.); Cholinergic Receptors; Chronic; Connexin 43; Connexins; Decubitus ulcer; Development; Electric Stimulation; Electrophysiology (science); Endoplasmic Reticulum; Exercise; Family; Functional disorder; Health; Heart Block; Human; Individual; Infection; Infusion procedures; Injury; Intestines; Ischemia; Kidney; L-Type Calcium Channels; Learning; Leg; Life; Life Expectancy; Life Style; Lipoproteins; Lung; Mediating; Mental Depression; Molecular; Morbidity - disease rate; Morphology; Muscarinics; Myocardial; Nerve Growth Factors; Neurons; Operating System; Oxygen; Oxygen Consumption; Paralysed; Paraplegia; Pathogenesis; Pericardial body location; Physiology; Predisposition; Proteins; Protocols documentation; Quality of life; Rattus; Recovery; Rehabilitation therapy; Reperfusion Therapy; Reporting; Research; Rest; Risk; Risk Factors; Ryanodine Receptor Calcium Release Channel; Severities; Sex Functioning; Sodium-Calcium Exchanger; Spinal Cord; Spinal cord injury; Stress; Structure of stellate ganglion; Testing; Therapeutic; Therapeutic Intervention; Thoracic spinal cord structure; Ventricular Arrhythmia; Ventricular Tachycardia; Walking; Workload; World War II; arm; assault; base; beta-adrenergic receptor; cardiovascular disorder risk; density; design; fitness; genetic regulatory protein; heart innervation; improved; insight; instrumentation; mRNA Expression; mortality; nerve supply; phospholamban; prevent; receptor; research study; response; sedentary

DESCRIPTION (provided by applicant): Prior to World War II, 80% of individuals with spinal cord injury (SCI) died within 3 years of the injury primarily due to kidney and pulmonary infections, pressure sores and depression. However, with the advent of antibiotic drugs and advancements in acute care and rehabilitation, the life expectancy of individuals with SCI has increased to near that for able-bodied individuals. However, cardiovascular disease is now a leading cause of death and morbidity for individuals with SCI. {In fact, morbidity and mortality from cardiovascular disease in individuals with chronic SCI exceeds that caused by renal and pulmonary complications, the primary cause of mortality in previous decades.} The risk for significant cardiovascular dysfunction is aggravated by the sedentary lifestyle of the typical individual with SCI. Specifically, individuals with SCI are placed at the lowest end of the human fitness spectrum. Therefore, exercise with the arms is often recommended for individuals with SCI, based on studies demonstrating improvements in aerobic capacity and lipoprotein profiles. The Centers for Disease Control has recommended further research to evaluate the efficacy of exercise to prevent the development of cardiovascular disease in individuals with SCI. {Understanding the mechanisms responsible for the increased susceptibility to cardiovascular disease as well as therapeutic interventions has the potential to impact the lives of millions of individuals and families with spinal cord injury. Therefore, we will test the hypothesis that mid-thoracic spinal cord injury increases cardiac nerve growth factor (NGF) content. The increased cardiac NGF content causes cardiac sympathetic-hyper-innervation. Specifically, the increased cardiac NGF content increases morphometric parameters (maximal diameter, cross- sectional area, density and dendritic arborization) of individual cardiac projecting sympathetic preganglionic neurons (SPNs), and postganglionic sympathetic neurons located within the stellate ganglion as well as increased cardiac sympathetic innervation density. This cardiac sympathetic-hyper-innervation, "cardiac rewiring", alters cardiac physiology and increases the susceptibility to ventricular arrhythmias. Furthermore, intra-pericardial infusion of an anti-NGF antibody, in T5 spinal cord transected rats, reduces cardiac sympathetic-hyper-innervation and reduces the susceptibility to ventricular arrhythmias. Similarly, daily exercise also reduces cardiac NGF content, reduces cardiac sympathetic-hyper-innervation and decreases the susceptibility to ventricular arrhythmias. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is now a leading cause of death and morbidity for individuals with spinal cord injury. In fact, morbidity and mortality from cardiovascular disease in individuals with chronic spinal cord injury exceeds that caused by renal and pulmonary complications, the primary cause of mortality in previous decades. We will investigate the mechanisms mediating the increased risk.

描述（由申请人提供）：第二次世界大战之前，80％的脊髓损伤患者（SCI）在受伤后的3年内死亡，主要是由于肾脏和肺部感染，压疮和抑郁症。然而，随着抗生素药物的出现以及急性护理和康复方面的进步，SCI患者的预期寿命已增加到靠近体重的人。但是，心血管疾病现在是SCI患者的死亡和发病率的主要原因。 {实际上，慢性SCI患者的心血管疾病的发病率和死亡率超过了肾脏和肺部并发症引起的，这是前几十年死亡的主要原因。}典型患者的久坐生活方式的严重心血管功能障碍的风险受到严重心血管功能障碍的风险。具体而言，具有SCI的个体位于人类健身谱的最低端。因此，基于证明有氧能力和脂蛋白谱的改善的研究，通常建议对SCI的个体进行锻炼。疾病控制中心建议进一步研究，以评估运动的疗效，以防止SCI患者的心血管疾病发展。 {了解导致对心血管疾病易感性增加的机制以及治疗性干预措施有可能影响数百万个脊髓损伤的人和家庭的生活。因此，我们将检验以下假设：胸腔中期脊髓损伤会增加心脏神经生长因子（NGF）含量。心脏NGF含量增加会引起心脏交感神经感染。具体而言，增加的心脏NGF含量增加了单个心脏投射交感神经前神经元（SPNS）的形态参数（最大直径，横截面面积，密度和树突状树木化），以及后旋格的交感神经元，以及位于销售中的symentic sonvernation sympteriac and Cardistic and Cardistic and cardiactiac contentiac and vation andvation nirvation nirvation vation nirvation v。这种心脏交感神经增压，“心脏重新布线”，改变心脏生理，并增加对心室心律不齐的敏感性。此外，在T5脊髓跨性别的大鼠中，对抗NGF抗体的腹膜内输注可减少心脏交感神经增压，并降低对心室心律不齐的敏感性。同样，每日运动还减少心脏NGF含量，减少心脏交感神经增压，并降低对心室心律失常的敏感性。 公共卫生相关性：心血管疾病现在是脊髓损伤患者的死亡和发病率的主要原因。实际上，患有慢性脊髓损伤患者心血管疾病的发病率和死亡率超过了肾脏和肺部并发症引起的，这是过去几十年来死亡的主要原因。我们将研究介导风险增加的机制。

项目成果

Cardiac spinal deafferentation reduces the susceptibility to sustained ventricular tachycardia in conscious rats.

心脊髓传入神经阻滞降低了清醒大鼠对持续性室性心动过速的易感性。

• DOI: 10.1152/ajpregu.00140.2011
• 发表时间: 2011
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Lujan,HeidiL;Krishnan,Sandhya;Dicarlo,StephenE
• 通讯作者: Dicarlo,StephenE

Targeted ablation of cardiac sympathetic neurons reduces resting, reflex and exercise-induced sympathetic activation in conscious rats.

• DOI: 10.1152/ajpheart.00095.2009
• 发表时间: 2009-05
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: H. Lujan;Gurunanthan Palani;Ying Chen;J. Peduzzi;S. DiCarlo

Myocardial ischemia, reperfusion, and infarction in chronically instrumented, intact, conscious, and unrestrained mice.

长期使用仪器、完整、有意识且不受约束的小鼠的心肌缺血、再灌注和梗塞。

• DOI: 10.1152/ajpregu.00095.2012
• 发表时间: 2012
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Lujan,HeidiL;Janbaih,Hussein;Feng,Han-Zhong;Jin,Jian-Ping;DiCarlo,StephenE
• 通讯作者: DiCarlo,StephenE

Partial hindlimb occlusion reduced the susceptibility to sustained ventricular tachycardia in conscious rats.

• DOI: 10.1177/1074248409340160
• 发表时间: 2009-09
• 期刊: Journal of cardiovascular pharmacology and therapeutics
• 影响因子: 2.6
• 作者: Lujan HL;DiCarlo SE
• 通讯作者: DiCarlo SE

Cardiac output, at rest and during exercise, before and during myocardial ischemia, reperfusion, and infarction in conscious mice.

清醒小鼠在休息和运动期间、心肌缺血、再灌注和梗塞之前和期间的心输出量。

• DOI: 10.1152/ajpregu.00517.2012
• 发表时间: 2013
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Lujan,HeidiL;DiCarlo,StephenE
• 通讯作者: DiCarlo,StephenE