Clin Res Cardiol (2022).

Renal denervation reduces atrial remodeling and risk of atrial fibrillation in a rat model of CKD
J. Wintrich1, S.-R. Selejan1, C. Ukena1, M. Mauz1, U. Lehnert1, P. Boor2, D. Wong2, B. M. Klinkhammer2, F. Mahfoud1, M. Hohl1, M. Böhm1
1Innere Medizin III - Kardiologie, Angiologie und internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar; 2Institut für Pathologie, Uniklinik Aachen, Aachen;

Background: Patients suffering from chronic kidney disease (CKD) have a higher risk of atrial fibrillation (AF) compared with the general population, although the exact pathophysiological mechanisms underlying the development of AF in CKD are incompletely understood. Furthermore, renal denervation (RDN) resulting in decreased sympathetic activity has been suggested to reduce both risk of spontaneous and inducible AF. Thus, this study aims at characterizing the influence of CKD on development of AF and assessing whether RDN may help to inhibit AF vulnerability in CKD.

Methods and Results: We compared left atrial (LA) fibrosis content by Sirius red staining from 14 patients with AF and concomitant CKD (GFR<60ml/min/1,73m2) to 16 AF-patients without CKD and 8 patients with sinus rhythm. LA fibrosis formation was significantly increased in patients with AF and CKD compared to AF without CKD or sinus rhythm. Furthermore, in a translational approach, male Sprague-Dawley rats were fed for 16 weeks with 0.25% adenine (AD) diet to mimic slow development of CKD. After four weeks, AD-treated rats were randomly subjected to either bilateral surgical renal denervation (RDN; AD-RDN rats; n=15) or sham surgery (AD-rats; n=15). Rats on normal chow served as control (Ctr; n=11). After 16 weeks, left atrial (LA) dimension and function were assessed by echocardiography, inducibility of arrhythmic episodes was tested by transesophageal burst-stimulation (20 burst-stimulations per animal), and in vivo epicardial mapping of the LA was performed under anesthesia. Compared with Ctr, both AD and AD-RDN rats exhibited higher plasma levels of creatinine as well as higher plasma levels of urea. Echocardiography revealed pronounced diastolic dysfunction as assessed by E/A ratio (Ctr: 1.10±0.02; AD: 1.75±0.11, p<0.001 vs Ctr; AD-RDN: 1.19±0.07, p<0.001 vs AD) and increased left atrial diameters (Ctr: 4.22±0.05 mm; AD: 4.76±0.06 mm, p<0.0001 vs Ctr; AD-RDN: 4.23±0.06 mm, p<0.0001 vs AD) in AD compared with Ctr and AD-RDN rats. Analogously, induction of AF by transesophageal burst stimulation was more likely in AD than in Ctr and AD-RDN rats. Moreover, in vivo epicardial mapping demonstrated impaired LA conduction latency (Ctr: 1.4±0.1 s/m; AD: 2.3±0.2 s/m, p<0.01 vs Ctr) and increased absolute conduction inhomogeneity (Ctr: 4.4±0.3 P5/P95; AD: 7.5±0.6 P5/P95, p<0.01 vs Ctr) in AD compared with Ctr. RDN-treatment decreased AF-susceptibility and ameliorated LA conduction latency (AD-RDN: 1.5±0.2 s/m, p<0.01 vs AD) and absolute conduction inhomogeneity (AD-RDN: 5.3±0.6 P5/P95, p<0.05 vs AD), independent of blood pressure reduction and renal function.

Conclusion: In a rat model, induction of CKD leads to atrial structural and electrophysiological remodeling. RDN resulting in decreased sympathetic activity may preserve atrial function and reduce the risk of atrial fibrillation in CKD independent of renal function and blood pressure reduction.