Indoxyl Sulfate Induces Ventricular Arrhythmias Attenuated by Secretoneurin in Right Ventricular Outflow Tract Cardiomyocytes

Overview

Journal Cardiovasc Toxicol

Date 2025 Jan 21

PMID 39838186

Authors

Yuan Hung

Chen-Chuan Cheng

Yen-Yu Lu

Shih-Yu Huang

Yao-Chang Chen

Fong-Jhih Lin

Wei-Shiang Lin

Yu-Hsun Kao

Yung-Kuo Lin

Shih-Ann Chen

Yi-Jen Chen

Affiliations

Soon will be listed here.

Abstract

Ventricular arrhythmias (VAs) are major causes of sudden cardiac death in chronic kidney disease (CKD) patients. Indoxyl sulfate (IS) is one common uremic toxin found in CKD patients. This study investigated whether IS could induce VAs via increasing right ventricular outflow tract (RVOT) arrhythmogenesis. Using conventional microelectrodes and whole-cell patch clamps, we studied the action potentials (APs) and ionic currents of isolated rabbit RVOT tissue preparations and single cardiomyocytes before and after IS (0.1 and 1.0 μM). Calcium fluorescence imaging was performed in RVOT cardiomyocytes treated with and without IS (1.0 μM) to evaluate the calcium transient and the calcium leak. In rabbit RVOT tissues, IS (0.1 and 1.0 μM) attenuated the contractility and shortened the AP durations in a dose-dependent manner. In addition, IS (0.1 and 1.0 μM) enhanced the pro-arrhythmia effects of isoproterenol (ISO, 1.0 μM) and rapid ventricular pacing in RVOT (before versus after ISO, 25% versus 83%, N = 12). In RVOT cardiomyocytes, IS (1.0 μM) significantly decreased the L-type calcium currents but increased the sodium-calcium exchanger and sodium window currents. Cardiomyocytes treated with IS (1.0 μM) had lower calcium transients but higher diastolic calcium and calcium leak than those without IS treatment. Pretreatment with secretoneurin (SN, 30 nM, a potent neuropeptide, suppressing CaMKII) or KN-93 (0.1 μM, a CaMKII inhibitor) prevented IS-induced ionic current changes and arrhythmogenesis. In conclusion, IS modulates RVOT electrophysiology and arrhythmogenesis via enhanced CaMKII activity, which is attenuated by SN, leading to a novel therapeutic target for CKD arrhythmias.

References

Alonso A, Lopez F, Matsushita K, Loehr L, Agarwal S, Chen L . Chronic kidney disease is associated with the incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2011; 123(25):2946-53. PMC: 3139978. DOI: 10.1161/CIRCULATIONAHA.111.020982. View

Hindricks G, Potpara T, Dagres N, Arbelo E, Bax J, Blomstrom-Lundqvist C . 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the.... Eur Heart J. 2020; 42(5):373-498. DOI: 10.1093/eurheartj/ehaa612. View

Huang S, Chen Y, Chen S, Chen Y, Lin Y . Uremic Toxins - Novel Arrhythmogenic Factor in Chronic Kidney Disease - Related Atrial Fibrillation. Acta Cardiol Sin. 2016; 32(3):259-64. PMC: 4884752. DOI: 10.6515/acs20151116a. View

Raff A, Meyer T, Hostetter T . New insights into uremic toxicity. Curr Opin Nephrol Hypertens. 2008; 17(6):560-5. DOI: 10.1097/MNH.0b013e32830f45b6. View

Sun C, Chang S, Wu M . Uremic toxins induce kidney fibrosis by activating intrarenal renin-angiotensin-aldosterone system associated epithelial-to-mesenchymal transition. PLoS One. 2012; 7(3):e34026. PMC: 3316590. DOI: 10.1371/journal.pone.0034026. View

Barreto F, Barreto D, Liabeuf S, Meert N, Glorieux G, Temmar M . Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol. 2009; 4(10):1551-8. PMC: 2758258. DOI: 10.2215/CJN.03980609. View

Lekawanvijit S, Adrahtas A, Kelly D, Kompa A, Wang B, Krum H . Does indoxyl sulfate, a uraemic toxin, have direct effects on cardiac fibroblasts and myocytes?. Eur Heart J. 2010; 31(14):1771-9. DOI: 10.1093/eurheartj/ehp574. View

Lekawanvijit S, Kompa A, Manabe M, Wang B, Langham R, Nishijima F . Chronic kidney disease-induced cardiac fibrosis is ameliorated by reducing circulating levels of a non-dialysable uremic toxin, indoxyl sulfate. PLoS One. 2012; 7(7):e41281. PMC: 3400638. DOI: 10.1371/journal.pone.0041281. View

Chen W, Chen Y, Hsieh M, Huang S, Kao Y, Chen Y . The uremic toxin indoxyl sulfate increases pulmonary vein and atrial arrhythmogenesis. J Cardiovasc Electrophysiol. 2014; 26(2):203-10. DOI: 10.1111/jce.12554. View

10.

Bleyer A, Hartman J, Brannon P, Reeves-Daniel A, Satko S, Russell G . Characteristics of sudden death in hemodialysis patients. Kidney Int. 2006; 69(12):2268-73. DOI: 10.1038/sj.ki.5000446. View

11.

Herzog C, Asinger R, Berger A, Charytan D, Diez J, Hart R . Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011; 80(6):572-86. DOI: 10.1038/ki.2011.223. View

12.

Robinson B, Zhang J, Morgenstern H, Bradbury B, Ng L, McCullough K . Worldwide, mortality risk is high soon after initiation of hemodialysis. Kidney Int. 2013; 85(1):158-65. PMC: 3877739. DOI: 10.1038/ki.2013.252. View

13.

Bonato F, Watanabe R, Lemos M, Cassiolato J, Wolf M, Canziani M . Asymptomatic Ventricular Arrhythmia and Clinical Outcomes in Chronic Kidney Disease: A Pilot Study. Cardiorenal Med. 2016; 7(1):66-73. PMC: 5159781. DOI: 10.1159/000449260. View

14.

Wan C, Herzog C, Zareba W, Szymkiewicz S . Sudden cardiac arrest in hemodialysis patients with wearable cardioverter defibrillator. Ann Noninvasive Electrocardiol. 2013; 19(3):247-57. PMC: 4034590. DOI: 10.1111/anec.12119. View

15.

Rogovoy N, Howell S, Lee T, Hamilton C, Perez-Alday E, Kabir M . Hemodialysis Procedure-Associated Autonomic Imbalance and Cardiac Arrhythmias: Insights From Continuous 14-Day ECG Monitoring. J Am Heart Assoc. 2019; 8(19):e013748. PMC: 6806026. DOI: 10.1161/JAHA.119.013748. View

16.

Hayashi H, Fujiki A, Tani M, Mizumaki K, Shimono M, Inoue H . Role of sympathovagal balance in the initiation of idiopathic ventricular tachycardia originating from right ventricular outflow tract. Pacing Clin Electrophysiol. 1997; 20(10 Pt 1):2371-7. DOI: 10.1111/j.1540-8159.1997.tb06073.x. View

17.

Kim R, Iwai S, Markowitz S, Shah B, Stein K, Lerman B . Clinical and electrophysiological spectrum of idiopathic ventricular outflow tract arrhythmias. J Am Coll Cardiol. 2007; 49(20):2035-43. DOI: 10.1016/j.jacc.2007.01.085. View

18.

Bottoni N, Quartieri F, Lolli G, Iori M, Manari A, Menozzi C . Sudden death in a patient with idiopathic right ventricular outflow tract arrhythmia. J Cardiovasc Med (Hagerstown). 2009; 10(10):801-3. DOI: 10.2459/JCM.0b013e32832cebbb. View

19.

Noda T, Shimizu W, Taguchi A, Aiba T, Satomi K, Suyama K . Malignant entity of idiopathic ventricular fibrillation and polymorphic ventricular tachycardia initiated by premature extrasystoles originating from the right ventricular outflow tract. J Am Coll Cardiol. 2005; 46(7):1288-94. DOI: 10.1016/j.jacc.2005.05.077. View

20.

Viskin S, Rosso R, Rogowski O, Belhassen B . The "short-coupled" variant of right ventricular outflow ventricular tachycardia: a not-so-benign form of benign ventricular tachycardia?. J Cardiovasc Electrophysiol. 2005; 16(8):912-6. DOI: 10.1111/j.1540-8167.2005.50040.x. View