Enhanced Mitochondrial Calcium Uptake Suppresses Atrial Fibrillation Associated With Metabolic Syndrome

J Am Coll Cardiol. 2022 Dec 6;80(23):2205-2219. doi: 10.1016/j.jacc.2022.09.041.


Background: Patients with metabolic syndrome (MetS) have an increased risk of atrial fibrillation (AF). Impaired Ca2+ homeostasis and mitochondrial dysfunction have emerged as an arrhythmogenic substrate in both patients and animal models of MetS. Whether impaired mitochondrial Ca2+ handling underlies AF associated with MetS remains poorly explored.

Objectives: The aim of this study was to determine the initial mechanisms related to AF susceptibility and mitochondrial dysfunction encountered in metabolic cardiomyopathy.

Methods: A total of 161 mice and 34 patients were studied. Mitochondrial Ca2+ and mitochondrial Ca2+ uniporter complex (MCUC) were investigated in right atrial tissue of patients with (n = 18) or without (n = 16) MetS and of C57Bl/6J mice fed with a high-fat sucrose diet (HFS) for 2 (n = 42) or 12 (n = 39) weeks. Susceptibility to AF was evaluated in isolated sinoatrial tissue and in vivo in mice.

Results: Increased expression of the MICUs subunits of the MCUC (1.00 ± 0.33 AU vs 1.29 ± 0.23 AU; P = 0.034) was associated with impaired mitochondrial Ca2+ uptake in patients (168.7 ± 31.3 nmol/min/mg vs 127.3 ± 18.4 nmol/min/mg; P = 0.026) and HFS mice (0.10 ± 0.04 ΔF/F0 × ms-1 vs 0.06 ± 0.03 ΔF/F0 × ms-1; P = 0.0086, and 0.15 ± 0.07 ΔF/F0 × ms-1 vs 0.046 ± 0.03 ΔF/F0 × ms-1; P = 0.0076 in 2- and 12-week HFS mice, respectively). HFS mice elicited a 70% increased susceptibility to AF. The MCUC agonist kaempferol restored MCUC activity in vitro and abolished the occurrence of AF in HFS mice.

Conclusions: Impaired MCUC activity and mitochondrial Ca2+ homeostasis from the early stage of metabolic cardiomyopathy in mice lead to AF. Given that similar defects in cardiac mitochondrial Ca2+ handling are present in MetS patients, the modulation of the MCUC activity represents an attractive antiarrhythmic strategy.

Keywords: atrial arrhythmias; calcium; diabetic cardiomyopathy; metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Arrhythmia Agents
  • Atrial Appendage*
  • Atrial Fibrillation* / etiology
  • Calcium
  • Metabolic Syndrome* / complications
  • Mice
  • Mice, Inbred C57BL


  • Calcium
  • Anti-Arrhythmia Agents