Aging-associated susceptibility to stress-induced ventricular arrhythmogenesis is attenuated by tetrodotoxin

Authors

Ekhson L. Holmuhamedov, Advocate Aurora Health
Praloy Chakraborty, Department of Cardiac Electrophysiology, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.Follow
Andrew Oberlin, Division of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN, 55905, USA.
Xiaoke Liu, Division of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN, 55905, USA.
Mohammed Yousufuddin, Division of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN, 55905, USA.
Win K. Shen, Division of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN, 55905, USA; Mayo Clinic Arizona, 13400 E. Shea Boulevard, Scottsdale, AZ, 85259, USA.
Andre Terzic, Division of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN, 55905, USA.
Arshad Jahangir, Advocate Aurora HealthFollow

Recommended Citation

Holmuhamedov EL, Chakraborty P, Oberlin A, et al. Aging-associated susceptibility to stress-induced ventricular arrhythmogenesis is attenuated by tetrodotoxin. Biochem Biophys Res Commun. 2022;623:44-50. doi:10.1016/j.bbrc.2022.07.040

Affiliations

Aurora Cardiovascular and Thoracic Services, Center for Advanced Atrial Fibrillation Therapies, Aurora Sinai/Aurora St. Luke's Medical Centers

Abstract

Aging is associated with increased prevalence of life-threatening ventricular arrhythmias, but mechanisms underlying higher susceptibility to arrhythmogenesis and means to prevent such arrhythmias under stress are not fully defined. We aimed to define differences in aging-associated susceptibility to ventricular fibrillation (VF) induction between young and aged hearts. VF induction was attempted in isolated perfused hearts of young (6-month) and aged (24-month-old) male Fischer-344 rats by rapid pacing before and following isoproterenol (1 μM) or global ischemia and reperfusion (I/R) injury with or without pretreatment with low-dose tetrodotoxin, a late sodium current blocker. At baseline, VF could not be induced; however, the susceptibility to inducible VF after isoproterenol and spontaneous VF following I/R was 6-fold and 3-fold higher, respectively, in old hearts (P < 0.05). Old animals had longer epicardial monophasic action potential at 90% repolarization (APD; P < 0.05) and displayed a loss of isoproterenol-induced shortening of APD present in the young. In isolated ventricular cardiomyocytes from older but not younger animals, 4-aminopyridine prolonged APD and induced early afterdepolarizations (EADs) and triggered activity with isoproterenol. Low-dose tetrodotoxin (0.5 μM) significantly shortened APD without altering action potential upstroke and prevented 4-aminopyridine-mediated APD prolongation, EADs, and triggered activity. Tetrodotoxin pretreatment prevented VF induction by pacing in isoproterenol-challenged hearts. Vulnerability to VF following I/R or catecholamine challenge is significantly increased in old hearts that display reduced repolarization reserve and increased propensity to EADs, triggered activity, and ventricular arrhythmogenesis that can be suppressed by low-dose tetrodotoxin, suggesting a role of slow sodium current in promoting arrhythmogenesis with aging.

Document Type

Article

PubMed ID

35870261