Atrial fibrillation is very common among the elderly and/or obese. While myocardial fibrosis is associated with atrial fibrillation, the exact mechanisms within atrial myocytes and surrounding non-myocytes are not fully understood. This review considers the potential roles of myocardial fibroblasts and myofibroblasts in fibrosis and modulating myocyte electrophysiology through electrotonic interactions. Coupling with (myo)fibroblasts in vitro and in silico prolonged myocyte action potential duration and caused resting depolarization; an optogenetic study has verified in vivo that fibroblasts depolarized when coupled myocytes produced action potentials. This review also introduces another non-myocyte which may modulate both myocardial (myo)fibroblasts and myocytes: epicardial adipose tissue. Epicardial adipocytes are in intimate contact with myocytes and (myo)fibroblasts and may infiltrate the myocardium. Adipocytes secrete numerous adipokines which modulate (myo)fibroblast and myocyte physiology. These adipokines are protective in healthy hearts, preventing inflammation and fibrosis. However, adipokines secreted from adipocytes may switch to pro-inflammatory and pro-fibrotic, associated with reactive oxygen species generation. Pro-fibrotic adipokines stimulate myofibroblast differentiation, causing pronounced fibrosis in the epicardial adipose tissue and the myocardium. Adipose tissue also influences myocyte electrophysiology, via the adipokines and/or through electrotonic interactions. Deeper understanding of the interactions between myocytes and non-myocytes is important to understand and manage atrial fibrillation.

Cardiovascular diseases (CVDs) are a significant burden globally and are especially prevalent in obese and/or diabetic populations. Epicardial adipose tissue (EAT) surrounding the heart has been implicated in the development of CVDs as EAT can shift from a protective to a maladaptive phenotype in diseased states. In diabetic and obese patients, an elevated EAT mass both secretes pro-fibrotic/pro-inflammatory adipokines and forms intramyocardial fibrofatty infiltrates. This narrative review considers the proposed pathophysiological roles of EAT in CVDs. Diabetes is associated with a disordered energy utilization in the heart, which promotes intramyocardial fat and structural remodeling. Fibrofatty infiltrates are associated with abnormal cardiomyocyte calcium handling and repolarization, increasing the probability of afterdepolarizations. The inflammatory phenotype also promotes lateralization of connexin (Cx) proteins, undermining unidirectional conduction. These changes are associated with conduction heterogeneity, together creating a substrate for atrial fibrillation (AF). EAT is also strongly implicated in coronary artery disease (CAD); inflammatory adipokines from peri-vascular fat can modulate intra-luminal homeostasis through an “outside-to-inside” mechanism. EAT is also a significant source of sympathetic neurotransmitters, which promote progressive diastolic dysfunction with eventual cardiac failure. Further investigations on the behavior of EAT in diabetic/obese patients with CVD could help elucidate the pathogenesis and uncover potential therapeutic targets.

Ischemic preconditioning (IPC) and activation of ATP-sensitive potassium channels (K_ATP) protect cardiac myocytes from ischemia reperfusion (IR) injury. We investigated the influence of IR injury, IPC and K_ATP in isolated rat cardiac fibroblasts. Hearts were removed under isoflurane anesthesia. IR was simulated in vitro by application and removal of paraffin oil over pelleted cells. Ischemia (30, 60 and 120 min) followed by 60 min reperfusion resulted in significant differentiation of fibroblasts into myofibroblasts in culture (mean % fibroblasts ± SEM in IR vs. time control: 12 ± 1% vs. 63 ± 2%, 30 min ischemia; 15 ± 3% vs. 71 ± 4%, 60 min ischemia; 8 ± 1% vs. 55 ± 2%, 120 min ischemia). IPC (15 min ischemia, 30 min reperfusion) significantly attenuated IR-induced fibroblast differentiation (52 ± 3%) compared to 60 min IR. IPC was mimicked by opening K_ATP with pinacidil (50 μM; 43 ± 6%) and by selectively opening mitochondrial K_ATP (mK_ATP) with diazoxide (100 μM; 53 ± 3%). Furthermore, IPC was attenuated by inhibiting K_ATP with glibenclamide (10 μM; 23 ± 5%) and by selectively blocking mK_ATP with 5-hydroxydecanoate (100 μM; 22 ± 9%). These results suggest that (a) IR injury evoked cardiac fibroblast to myofibroblast differentiation, (b) IPC attenuated IR-induced fibroblast differentiation, (c) K_ATP were involved in IPC and (d) this protection involved selective activation of mK_ATP.