Atrial Fibrillation and Diabetes Mellitus: Dangerous Liaisons or Innocent Bystanders?

Atrial fibrillation (AF) is the most common arrhythmia in adults and diabetes mellitus (DM) is a major risk factor for cardiovascular diseases. However, the relationship between both pathologies has not been fully documented and new evidence supports the existence of direct and independent links. In the myocardium, a combination of structural, electrical, and autonomic remodeling may lead to AF. Importantly, patients with AF and DM showed more dramatic alterations than those with AF or DM alone, particularly in mitochondrial respiration and atrial remodeling, which alters conductivity, thrombogenesis, and contractile function. In AF and DM, elevations of cytosolic Ca²⁺ and accumulation of extra cellular matrix (ECM) proteins at the interstitium can promote delayed afterdepolarizations. The DM-associated low-grade inflammation and deposition/infiltration of epicardial adipose tissue (EAT) enforce abnormalities in Ca²⁺ handling and in excitation-contraction coupling, leading to atrial myopathy. This atrial enlargement and the reduction in passive emptying volume and fraction can be key for AF maintenance and re-entry. Moreover, the stored EAT can prolong action of potential durations and progression from paroxysmal to persistent AF. In this way, DM may increase the risk of thrombogenesis as a consequence of increased glycation and oxidation of fibrinogen and plasminogen, impairing plasmin conversion and resistance to fibrinolysis. Additionally, the DM-associated autonomic remodeling may also initiate AF and its re-entry. Finally, further evidence of DM influence on AF development and maintenance are based on the anti-arrhythmogenic effects of certain anti-diabetic drugs like SGLT2 inhibitors. Therefore, AF and DM may share molecular alterations related to Ca²⁺ mobility, mitochondrial function and ECM composition that induce atrial remodeling and defects in autonomic stimulation and conductivity. Likely, some specific therapies could work against the associated cardiac damage to AF and/or DM.