Dipeptidyl peptidase 4 (DPP-4) inhibitors have recently been reported to exhibit additional cardioprotective effects; however, their effect in atrial remodeling, such as in atrial fibrillation (AF), remains unclear. In this study, the effect of linagliptin on atrial electrical and structural remodeling was evaluated in a canine AF model. Sixteen beagle dogs with 3-week atrial rapid stimulation were divided into the linagliptin group (9 mg/kg/day, n = 8) and pacing control group (n = 8). Three additional dogs without rapid pacing were assigned into non-pacing group, which was used as sham in this study. In the dogs with rapid pacing, the atrial effective refractory period (AERP), conduction velocity (CV), and AF inducibility were evaluated and blood was sampled every week. After the entire protocol, atrial tissue was sampled for histological examinations using HE, Azan, and dihydroethidium (DHE) staining to evaluate any tissue damage or oxidative stress. The pacing control group exhibited a gradual AERP shortening and CV decrease along the time course as previously reported. In the linagliptin group, the AERP shortening was not affected, but the CV decrease was suppressed in comparison to the control group (p < 0.05). The AF inducibility was increased in the control group and suppressed in the linagliptin group (p < 0.05). The control group exhibited tissue fibrosis, the degree of which was suppressed in the linagliptin group. DHE staining exhibited suppression of the reactive oxygen species expression in the linagliptin group in comparison to the pacing control group. Linagliptin, a DPP-4-inhibitor, suppressed the AF inducibility, CV decrease, and overexpression of oxidative stress in the canine AF model. Such suppressive effects of linagliptin on AF in the canine model may possibly be related to the anti-oxidative effect.
Keywords: Atrial fibrillation; Atrial remodeling; Dipeptidyl peptidase 4 inhibitor; Linagliptin; Oxidative stress.