Philipp Markwirth, Simina-Ramona Selejan, Mathias Hohl, Stefan J Schunk, Andreas Müller, Stefan Wagenpfeil, Lea Wagmann, Florian Kahles, Mert Tokcan, Markus Therre, Emiel P C van der Vorst, Matthias Rau, Heidi Noels, Julia Wollenhaupt, Felix Mahfoud, Michael Böhm
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引用次数: 0
Abstract
Background: Chronic kidney disease (CKD) is an independent cardiovascular risk factor. Patients with CKD develop uremic cardiomyopathy characterized by activation of the sympathetic nervous system, left ventricular hypertrophy, and accumulation of uremic toxins such as indoxyl sulfate (IS). The aim of this study was to assess the effects of renal denervation (RDN) on uremic cardiomyopathy in a rat model of CKD.
Methods: Sprague-Dawley rats were fed a standard chow (control group, n=6) or a 0.25% adenine-enriched chow (n=16) for 16 weeks to induce CKD. After 4 weeks, CKD rats with CKD were subjected to bilateral RDN (AD-RDN, n=8) or to sham operation (AD, n=8). Blood pressure measurements, echocardiography, and cardiac magnetic resonance imaging were deployed during the experiment. Left ventricular hypertrophy was evaluated histologically. IS was measured using ELISA. In H9C2 cardiomyoblasts, the hypertrophic effects of IS were characterized in vitro.
Results: In AD rats, left ventricular septal wall thickness (2.37±0.036 versus 1.91±0.014 mm in CTRL, P <0.0001), E/A ratio, and cardiomyocyte size were significantly increased. Following RDN, left ventricular wall thickness (P <0.0001 versus AD), E/A ratio (P <0.0001 versus AD), and myocyte hypertrophy were significantly reduced. Plasma IS was increased in AD (0.79±0.07 versus 0.2±0.12 μg/mg in the control group, P=0.0044) and reduced in AD-RDN (P=0.0073 versus AD). Urinary IS remained unchanged after RDN, whereas hepatic concentration of IS decreased after RDN (P=0.023). Plasma IS correlated with left ventricular hypertrophy (r=0.779, P <0.0001). Stimulation of H9C2 cardiomyoblasts with IS or serum from AD rats showed an increase in cell size (P=0.0015), whereas AD-RDN serum showed no effect.
Conclusions: In a rat model of CKD, improved cardiac function following RDN was associated with reduced plasma concentrations of IS. To the present, IS remains a persistent clinical concern in patients with CKD due to its inefficient removal by conventional hemodialysis and its significant role in promoting both kidney and myocardial disease. Thus, RDN may ameliorate uremic cardiomyopathy by reducing IS and potentially represents a treatment option for patients with CKD and cardiovascular disease. Clinical trials are warranted to investigate the effects of RDN on cardiovascular outcomes in patients with CKD.
背景：慢性肾脏疾病（CKD）是一种独立的心血管危险因素。CKD患者发展为尿毒症心肌病，其特征是交感神经系统激活，左心室肥厚，尿毒症毒素如硫酸吲哚酚（IS）的积累。本研究的目的是评估肾去神经支配（RDN）对CKD大鼠模型尿毒症心肌病的影响。方法：采用标准鼠粮（对照组，n=6）或0.25%腺嘌呤富集鼠粮（n=16），连续16周诱导sd。4周后，CKD大鼠进行双侧RDN （AD-RDN, n=8）或假手术（AD, n=8）。在实验期间进行血压测量、超声心动图和心脏磁共振成像。组织学评价左室肥厚。ELISA法测定IS。体外观察IS对H9C2型心肌细胞的增生性作用。结果：AD大鼠左室间隔壁厚度（对照组为2.37±0.036 mm，对照组为1.91±0.014 mm, P P P P=0.0044）， AD- rdn组左室间隔壁厚度减少（P=0.0073， AD组）。RDN后尿IS保持不变，而RDN后肝脏IS浓度下降（P=0.023）。血浆IS与左室肥厚相关（r=0.779， P=0.0015），而血清AD-RDN无影响。结论：在CKD大鼠模型中，RDN后心功能的改善与血浆IS浓度的降低有关。迄今为止，IS仍是CKD患者持续关注的临床问题，因为常规血液透析不能有效清除IS，而且IS在促进肾脏和心肌疾病方面具有重要作用。因此，RDN可能通过减少IS来改善尿毒症心肌病，并可能代表CKD和心血管疾病患者的治疗选择。临床试验需要研究RDN对CKD患者心血管预后的影响。
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As an Open Access journal, JAHA - Journal of the American Heart Association is rapidly and freely available, accelerating the translation of strong science into effective practice.
JAHA is an authoritative, peer-reviewed Open Access journal focusing on cardiovascular and cerebrovascular disease. JAHA provides a global forum for basic and clinical research and timely reviews on cardiovascular disease and stroke. As an Open Access journal, its content is free on publication to read, download, and share, accelerating the translation of strong science into effective practice.
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