Novel preventive effect of isorhamnetin on electrical and structural remodeling in atrial fibrillation

Clin Sci (Lond). 2022 Dec 22;136(24):1831-1849. doi: 10.1042/CS20220319.


Isorhamnetin, a natural flavonoid, has strong antioxidant and antifibrotic effects, and a regulatory effect against Ca2+-handling. Atrial remodeling due to fibrosis and abnormal intracellular Ca2+ activities contributes to initiation and persistence of atrial fibrillation (AF). The present study investigated the effect of isorhamnetin on angiotensin II (AngII)-induced AF in mice. Wild-type male mice (C57BL/6J, 8 weeks old) were assigned to three groups: (1) control group, (2) AngII-treated group, and (3) AngII- and isorhamnetin-treated group. AngII (1000 ng/kg/min) and isorhamnetin (5 mg/kg) were administered continuously via an implantable osmotic pump for two weeks and intraperitoneally one week before initiating AngII administration, respectively. AF induction and electrophysiological studies, Ca2+ imaging with isolated atrial myocytes and HL-1 cells, and action potential duration (APD) measurements using atrial tissue and HL-1 cells were performed. AF-related molecule expression was assessed and histopathological examination was performed. Isorhamnetin decreased AF inducibility compared with the AngII group and restored AngII-induced atrial effective refractory period prolongation. Isorhamnetin eliminated abnormal diastolic intracellular Ca2+ activities induced by AngII. Isorhamnetin also abrogated AngII-induced APD prolongation and abnormal Ca2+ loading in HL-1 cells. Furthermore, isorhamnetin strongly attenuated AngII-induced left atrial enlargement and atrial fibrosis. AngII-induced elevated expression of AF-associated molecules, such as ox-CaMKII, p-RyR2, p-JNK, p-ERK, and TRPC3/6, was improved by isorhamnetin treatment. The findings of the present study suggest that isorhamnetin prevents AngII-induced AF vulnerability and arrhythmogenic atrial remodeling, highlighting its therapeutic potential as an anti-arrhythmogenic pharmaceutical or dietary supplement.

Keywords: Ca2+-handling; CaMKII; MAPK; TRPC; atrial fibrillation; isorhamnetin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / metabolism
  • Animals
  • Atrial Fibrillation* / drug therapy
  • Atrial Fibrillation* / prevention & control
  • Atrial Remodeling*
  • Calcium / metabolism
  • Heart Atria / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Cardiac / metabolism


  • 3-methylquercetin
  • Calcium
  • Angiotensin II