Hohl Mathias, Selejan Simina-Ramona, Wintrich Jan, Lehnert Ulrike, Speer Thimoteus, Schneider Clara, Mauz Muriel, Markwirth Philipp, Wong Dickson W L, Boor Peter, Kazakov Andrey, Mollenhauer Martin, Linz Benedikt, Klinkhammer Barbara Mara, Hübner Ulrich, Ukena Christian, Moellmann Julia, Lehrke Michael, Wagenpfeil Stefan, Werner Christian, Linz Dominik, Mahfoud Felix, Böhm Michael
Department of Internal Medicine III, Saarland University Hospital and Saarland University, Homburg/Saar, Germany (M.H., S.-R.S., J.W., U.L., C.S., M. Mauz, P.M., A.K., C.U., C.W., D.L., F.M., M.B.).
Klinik für Innere Medizin IV, Universität des Saarlandes, Homburg/Saar, Germany (T.S.).
Circ Res. 2022 Mar 18;130(6):814-828. doi: 10.1161/CIRCRESAHA.121.320104. Epub 2022 Feb 8.
In patients with chronic kidney disease (CKD), atrial fibrillation (AF) is highly prevalent and represents a major risk factor for stroke and death. CKD is associated with atrial proarrhythmic remodeling and activation of the sympathetic nervous system. Whether reduction of the sympathetic nerve activity by renal denervation (RDN) inhibits AF vulnerability in CKD is unknown.
Left atrial (LA) fibrosis was analyzed in samples from patients with AF and concomitant CKD (estimated glomerular filtration rate [eGFR], <60 mL/min per 1.73 m) using picrosirius red and compared with AF patients without CKD and patients with sinus rhythm with and without CKD. In a translational approach, male Sprague Dawley rats were fed with 0.25% adenine (AD)-containing chow for 16 weeks to induce CKD. At week 5, AD-fed rats underwent RDN or sham operation (AD). Rats on normal chow served as control. After 16 weeks, cardiac function and AF susceptibility were assessed by echocardiography, radiotelemetry, electrophysiological mapping, and burst stimulation, respectively. LA tissue was histologically analyzed for sympathetic innervation using tyrosine hydroxylase staining, and LA fibrosis was determined using picrosirius red.
Sirius red staining demonstrated significantly increased LA fibrosis in patients with AF+CKD compared with AF without CKD or sinus rhythm. In rats, AD demonstrated LA structural changes with enhanced sympathetic innervation compared with control. In AD, LA enlargement was associated with prolonged duration of induced AF episodes, impaired LA conduction latency, and increased absolute conduction inhomogeneity. RDN treatment improved LA remodeling and reduced LA diameter compared with sham-operated AD. Furthermore, RDN decreased AF susceptibility and ameliorated LA conduction latency and absolute conduction inhomogeneity, independent of blood pressure reduction and renal function.
In an experimental rat model of CKD, RDN inhibited progression of atrial structural and electrophysiological remodeling. Therefore, RDN represents a potential therapeutic tool to reduce the risk of AF in CKD, independent of changes in renal function and blood pressure.
在慢性肾脏病（CKD）患者中，心房颤动（AF）非常普遍，是中风和死亡的主要危险因素。CKD与心房促心律失常重塑及交感神经系统激活有关。肾脏去神经支配（RDN）降低交感神经活性是否能抑制CKD患者的AF易感性尚不清楚。
使用天狼星红对伴有CKD（估计肾小球滤过率[eGFR]＜60 mL/min/1.73 m²）的AF患者样本中的左心房（LA）纤维化进行分析，并与无CKD的AF患者以及有和无CKD的窦性心律患者进行比较。采用转化研究方法，给雄性Sprague Dawley大鼠喂食含0.25%腺嘌呤（AD）的饲料16周以诱导CKD。在第5周时，给喂食AD的大鼠进行RDN或假手术（AD）。以正常饲料喂养的大鼠作为对照。16周后，分别通过超声心动图、无线电遥测、电生理标测和猝发刺激评估心脏功能和AF易感性。使用酪氨酸羟化酶染色对LA组织进行组织学分析以检测交感神经支配情况，并用天狼星红测定LA纤维化程度。
天狼星红染色显示，与无CKD的AF患者或窦性心律患者相比，AF + CKD患者的LA纤维化显著增加。在大鼠中，与对照相比，AD显示LA结构改变且交感神经支配增强。在AD组中，LA增大与诱导的AF发作持续时间延长、LA传导延迟受损以及绝对传导不均一性增加有关。与假手术的AD组相比，RDN治疗改善了LA重塑并减小了LA直径。此外，RDN降低了AF易感性，改善了LA传导延迟和绝对传导不均一性，且与血压降低和肾功能无关。
在CKD实验大鼠模型中，RDN抑制了心房结构和电生理重塑的进展。因此，RDN是一种潜在的治疗手段，可降低CKD患者发生AF的风险，且与肾功能和血压变化无关。
