Search

Background Obstructive sleep apnea (OSA) is characterized by intermittent negative thoracic pressure fluctuations and intermittent hypoxemic events. Recent findings associate OSA with impaired ventricular repolarization during sleep and increased risk of sudden cardiac death, which may have special implications for Long-QT-2-syndrome patients. Therefore, we elucidated changes in ventricular repolarization and electromechanical coupling (electromechanical window; EMW) during either obstructive respiratory events simulated by intermittent negative upper airway pressure (INAP) or hypoxemic events simulated by intermittent hypoxia (IH) in vehicle (VEH) and dofetilide (DOF) treated pigs, as a simulation of drug induced Long-QT-2 syndrome. Methods In sedated spontaneously breathing pigs, either VEH or DOF (50 μg/kg) was perfused and INAP was applied by a negative pressure device connected to the intubation tube. For IH-application the device was connected and left turned off. INAP or IH was maintained for 75 seconds followed by a ten-minute resting period. In order to evaluate the electromechanical window, the time difference between electrical (QT-duration) and mechanical systole (Q-wave to the end of left ventricular pressure signal, QLVPend) was measured before (pre-INAP/-IH), during and 60 seconds after INAP/IH (post-INAP/-IH). Incidence rates of premature ventricular contractions (PVC) and ventricular tachycardia were compared pre- to post-INAP/-IH. Results In VEH-pigs, EMW shortened throughout INAP and post-INAP periods steadily (VEH: pre-INAP: 81.69±2.31ms; INAP: 55.65±6.13ms; post-INAP: 38±8.89ms. p=0.008). EMW shortening during post-INAP was associated with an increase in PVCs (VEH: pre-INAP 5.41±1.87 vs. post-INAP 26.5±8.15; p=0.04). In DOF-pigs, INAP-associated EMW-shortening was further potentiated (DOF: pre-INAP: 61.16±7.18ms; INAP: 38.09±9.84ms; post-INAP: 14.93±9.24ms. p=0.016), which was associated with an increase in PVCs (DOF: pre-INAP 4.75±2.36 vs. post-INAP 36.58±10.92; p=0.017). Administration of Atenolol could prevent post-INAP shortening of the EMW and decrease counts of premature ventricular contractions. While desaturations were comparable in INAP and IH, IH did not result in EMW-shortening or increased arrhythmia risk. Conclusion Transient dissociation of the ventricular electromechanical coupling during a simulated obstructive apnea, but not during IH, creates a dynamic and sympathetically driven arrhythmogenic substrate. Apnea associated ventricular electromechanical uncoupling was aggravated in a drug-induced Long-QT-2 simulation. Whether OSA represents a modifiable arrhythmogenic risk factor in Long-QT-2-patients warrants further studies. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Novo nordisk fonden

Background In obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase vagal tone and adenosine release, potentially resulting in an increased acetylcholine-regulated potassium current (IK,ACh). Here we elucidated acute atrial electrophysiological effects of obstructive respiratory events simulated by intermittent negative upper airway pressure (INAP) and the role of atrial IKACh activation by A1-receptor and M2-receptor activation. Methods In sedated spontaneously breathing rats (2% isoflurane), either IK,ACh-inhibitor (XAF-1407: 1mg/kg), M2-receptor inhibitor (atropine; 1μg/kg), A1-receptor inhibitor (Rolofylline; 1μg/kg) or a buffer-based vehicle was perfused (Control). INAP was applied non-invasively by a negative pressure device 14 times throughout 70 minutes. Simulated apneas were maintained for one minute with a four minute resting period. Atrial effective refractory period (AERP) and atrial activation time were acquired by a programmed atrial pacing protocol before, during and after applied INAP throughout the study. Results Independent of IK,Ach-inhibition, single INAP applications prolonged transiently atrial activation times (Control: INAP vs. pre-INAP p=0.034; XAF-1407: INAP vs. pre-INAP p=0.039). In control-rats, seventy minutes of repetitive INAP decreased AERP by 15.45±0.06% (vs. baseline p=0.0015), which was reversible upon 1 hour of recovery. AERP shortening correlated with the cumulative pressure applied per body weight (Pearson r=−0.773; p=0.025). Whilst only XAF-1407 and atropine increased baseline AERP, all drug interventions, XAF-1407, atropine and Rolofylline could prevent INAP-associated AERP shortening (end INAP-protocol vs. respective baseline XAF-1407 p=0.994; atropine p=0.984; Rolofylline p=0.951). Drops in oxygen saturation and applied INAP were comparable in all groups. Conclusion Short-term simulated OSA is associated with progressive AERP shortening, which was determined by the cumulative negative airway pressure applied. This potentially represents an important insight in future OSA treatment. Pharmacological IK,ACh inhibition prevented INAP-associated AERP-shortening suggesting an involvement in acute atrial arrhythmogenesis in OSA. However, if IK,Ach and its potential upstream activating A1- and M2-pathway pose a pharmacological treatment target for OSA-patients with AF, requires further investigation. Funding Acknowledgement Type of funding source: None

Introduction Obesity and enhanced inflammatory response are two independent risk factors involved in the pathogenesis of atrial fibrillation (AF). Components of the NLRP3 inflammasome have been found to be expressed in cardiomyocytes and cardiac fibroblasts and that increased inflammasome activation contributes to the pathogenesis of AF. The NLRP3 inflammasome is a multi-protein signaling complex that is activated in two steps: 1st) a priming event that includes a NFκB-activating stimuli which increases the expression of pro-inflammatory cytokines, and 2nd) a triggering event that includes the assembly of the inflammasome complex and activation of caspase-1 which promotes the production of pro-inflammatory cytokines like interleukin 1 beta (IL-1b). Purpose We used a sheep model of sustained obesity to characterize the association between atrial myocardial fat infiltration, atrial activation of the NLRP3 inflammasome and the development of an atrial arrhythmogenic substrate for AF. Methods Eight sheep were fed ad libitum calorie-dense diet over 40 weeks to gain weight and were maintained in this state of sustained obesity for another 40 weeks. Eight lean, weight-controlled and aged-matched sheep served as control. Atrial fat infiltration was determined by oil-red staining and NLRP3 inflammasome activation was assessed by immunoblot in atrial whole-tissue lysate. Atrial effective refractory periods (aERPs) were evaluated (twice diastolic threshold, cycle length (CL) of 400 ms, S1S2 -protocol). Results Sustained obesity was associated with increased atrial fat infiltration (lean: 0.8±0.3% vs. obese: 2.3±1.2%, p=0.1) and shorter aERP (lean: 169±22ms vs. obese: 138±26ms, p=0.03). Protein levels of caspase-1 and mature IL-1β were significantly enhanced (p=0.04 and p=0.01, respectively). Further shortening of aERP correlated with increasing atrial protein levels of caspase-1 (r=0.59, p=0.02). In contrast, levels of TNFα and NFκB were not significantly changed in atria of sheep with sustained obesity. Conclusions Sustained obesity is associated with increased expression of NLRP3 inflammasome-related proteins and the development of an arrhythmogenic substrate for AF. Our study suggest that the increased activity is due to increased triggering, rather than increased gene transcription. Whether NLRP3 inflammasome activation represents a modifiable target to prevent AF in obesity warrants further study.