Wang Han-Jun, Wang Wei, Cornish Kurtis G, Rozanski George J, Zucker Irving H
From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha.
Hypertension. 2014 Oct;64(4):745-55. doi: 10.1161/HYPERTENSIONAHA.114.03699. Epub 2014 Jun 30.
The enhanced cardiac sympathetic afferent reflex (CSAR) contributes to the exaggerated sympathoexcitation in chronic heart failure (CHF). Increased sympathoexcitation is positively related to mortality in patients with CHF. However, the potential beneficial effects of chronic CSAR deletion on cardiac and autonomic function in CHF have not been previously explored. Here, we determined the effects of chronic CSAR deletion on cardiac remodeling and autonomic dysfunction in CHF. To delete the transient receptor potential vanilloid 1 receptor-expressing CSAR afferents selectively, epicardial application of resiniferatoxin (50 μg/mL), an ultrapotent analog of capsaicin, was performed during myocardium infarction surgery in rats. This procedure largely abolished the enhanced CSAR, prevented the exaggerated renal and cardiac sympathetic nerve activity and improved baroreflex sensitivity in CHF rats. Most importantly, we found that epicardial application of resiniferatoxin largely prevented the elevated left ventricle end-diastolic pressure, lung edema, and cardiac hypertrophy, partially reduced left ventricular dimensions in the failing heart, and increased cardiac contractile reserve in response to β-adrenergic receptor stimulation with isoproterenol in CHF rats. Molecular evidence showed that resiniferatoxin attenuated cardiac fibrosis and apoptosis and reduced expression of fibrotic markers and transforming growth factor-β receptor I in CHF rats. Pressure-volume loop analysis showed that resiniferatoxin reduced the end-diastolic pressure volume relationships in CHF rats, indicating improved cardiac compliance. In summary, cardiac sympathetic afferent deletion exhibits protective effects against deleterious cardiac remodeling and autonomic dysfunction in CHF. These data suggest a potential new paradigm and therapeutic potential in the management of CHF.
增强的心脏交感神经传入反射（CSAR）促成了慢性心力衰竭（CHF）中过度的交感神经兴奋。交感神经兴奋增强与CHF患者的死亡率呈正相关。然而，慢性CSAR缺失对CHF心脏和自主神经功能的潜在有益作用此前尚未被探索。在此，我们确定了慢性CSAR缺失对CHF心脏重塑和自主神经功能障碍的影响。为了选择性地消除表达瞬时受体电位香草酸受体1的CSAR传入神经，在大鼠心肌梗死手术期间，在心外膜应用树脂毒素（50μg/mL），它是辣椒素的超效类似物。该操作在很大程度上消除了增强的CSAR，防止了肾和心脏交感神经活动的过度增强，并改善了CHF大鼠的压力反射敏感性。最重要的是，我们发现心外膜应用树脂毒素在很大程度上预防了左心室舒张末期压力升高、肺水肿和心脏肥大，部分减小了衰竭心脏的左心室尺寸，并增加了CHF大鼠在异丙肾上腺素刺激β-肾上腺素能受体时的心脏收缩储备。分子证据表明，树脂毒素减轻了CHF大鼠的心脏纤维化和细胞凋亡，并降低了纤维化标志物和转化生长因子-β受体I的表达。压力-容积环分析表明，树脂毒素降低了CHF大鼠的舒张末期压力-容积关系，表明心脏顺应性得到改善。总之,心脏交感神经传入缺失对CHF有害的心脏重塑和自主神经功能障碍具有保护作用。这些数据提示了CHF治疗中一种潜在的新范式和治疗潜力。
