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BACKGROUND Obstructive sleep apnea is associated with increased risk of sudden cardiac death.OBJECTIVE The purpose of this study was to elucidate changes in ventricular repolarization and electromechanical interaction during obstructive respiratory events simulated by intermittent negative upper airway pressure (INAP) in pigs. We also investigated the effect of a reduced repolarization reserve in drug-induced long QT (LQT) following INAP-induced changes in ventricular repolarization.METHODS In sedated spontaneously breathing pigs, 75 seconds of INAP was applied by a negative pressure device connected to the endotracheal tube. Ventricular electromechanical coupling was determined by the electromechanical window (EMW) before (preINAP), during (INAP), and after INAP (post-INAP). Incidence rates of premature ventricular contractions (PVCs) were measured respectively. A drug-induced LQT was modeled by treating the pigs with the hERG1 Mocker dofetilide (DOE).RESULTS Whereas QT interval increased during and decreased after INAP (pre-INAP: 273 +/- 5 ms; INAP 281 +/- 6 ms; post-INAP 254 +/- 9 ms), EMW shortened progressively throughout INAP and post-INAP periods (pre-INAP 81 +/- 4 ms; post-INAP 44 +/- 7 ms). DOF shortened EMW at baseline. Throughout INAP, EMW decreased in a comparable fashion as before DOF (pre-INAP/+DOF 61 +/- 7 ms; post-INAP/+DOF 14 +/- 9 ms) but resulted in shorter absolute EMW levels. Short EMW levels were associated with increased occurrence of PVCs (pre-INAP 7 +/- 2 ms vs post-INAP 26 +/- 6 ms; P = .02), which were potentiated in DOF pigs (pre-INAP/+DOF 5 +/- 2 ms vs post-INAP/+DOF 40 +/- 8 ms; P = .006). Administration of atenolol prevented post-INAP EMW shortening and decreased occurrence of PVCs.CONCLUSION Transient dissociation of ventricular electromechanical coupling during simulated obstructive respiratory events creates a dynamic ventricular arrhythmogenic substrate, which is sympathetically mediated and aggravated by drug-induced LQT.

Background: In obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase atrial fibrillation (AF) susceptibility by cholinergic activation.Objective: To investigate short-term atrial electrophysiological consequences of obstructive respiratory events, simulated by intermittent negative upper airway pressure (INAP), and the role of atrial acetylcholine-regulated potassium current (I K,ACh) activated by the M2 receptor.Methods: In sedated (2% isoflurane), spontaneously breathing rats, INAP was applied noninvasively by a negative pressure device for 1 minute, followed by a resting period of 4 minutes. INAP was applied repeatedly throughout 70 minutes, followed by a 2-hour recovery period. Atrial effective refractory period (AERP) and AF inducibility were determined throughout the protocol. To study INAP-induced I K,ACh activation, protein levels of protein kinase C (PKCƐ) were determined in membrane and cytosolic fractions of left atrial (LA) tissue by Western blotting. Moreover, an I K,ACh inhibitor (XAF-1407: 1 mg/kg) and a muscarinic receptor inhibitor (atropine: 1 μg/kg) were investigated.Results: In vehicle-treated rats, repetitive INAP shortened AERP (37 ± 3 ms vs baseline 44 ± 3 ms; P = .001) and increased LA membrane PKCƐ content relative to cytosolic levels. Upon INAP recovery, ratio of PKCƐ membrane to cytosol content normalized and INAP-induced AERP shortening reversed. Both XAF-1407 and atropine increased baseline AERP (control vs XAF-1407: 61 ± 4 ms; P > .001 and control vs atropine: 58 ± 3 ms; P = .011) and abolished INAP-associated AERP shortening.Conclusion: Short-term simulated OSA is associated with a progressive, but transient, AERP shortening and a PKCƐ translocation to LA membrane. Pharmacological I K,ACh and muscarinic receptor inhibition prevented transient INAP-induced AERP shortening, suggesting an involvement of I K,ACh in the transient arrhythmogenic AF substrate in OSA.

Highlights • Persistent atrial fibrillation is associated with increased fibroblast accumulation. • Six weeks of persistent AF is not associated with structural remodeling. • Fibroblasts are potentially contributing to alteration in atrial electrophysiology., Background Fibroblasts maintain the extracellular matrix homeostasis and may couple to cardiomyocytes through gap junctions and thereby increase the susceptibility to slow conduction and cardiac arrhythmias, such as atrial fibrillation (AF). In this study, we used an equine model of persistent AF to characterize structural changes and the role of fibroblasts in the development of an arrhythmogenic substrate for AF. Material and methods Eleven horses were subjected to atrial tachypacing until self-sustained AF developed and were kept in AF for six weeks. Horses in sinus rhythm (SR) served as control. In terminal open-chest experiments conduction velocity (CV) was measured. Tissue was harvested and stained from selected sites. Automated image analysis was performed to assess fibrosis, fibroblasts, capillaries and various cardiomyocyte characteristics. Results Horses in SR showed a rate-dependent slowing of CV, while in horses with persistent AF this rate-dependency was completely abolished (CV•basic cycle length relation p = 0.0295). Overall and interstitial amounts of fibrosis were unchanged, but an increased fibroblast count was found in left atrial appendage, Bachmann's bundle, intraatrial septum and pulmonary veins (p

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

A variety of life-threating arrhythmias are caused by mutations in the cardiac voltage-gated sodium channel encoded by the SCN5A gene. In this study, we report a novel loss-of-function SCN5A variant, p.Ile1343Val (c.4027A>G), identified in a 42-year-old proband who presented with an unusual ECG with abnormal repolarization with biphasic T-waves in anteroseptal leads, persistent atrial fibrillation (AF), intermittent left bundle branch block (LBBB), and reversible cardiomyopathy. The patient did not meet the diagnostic criteria for Brugada syndrome, long QT syndrome, or any other known SCN5A-associated phenotype. Characterization of the biophysical properties of the variant by in vitro patch clamp experiments revealed a reduced Na+ current with no effect on the inactivation kinetics of the channel. This loss-of-function of Na+ current could explain the intermittent LBBB as well as the AF. In conclusion, we describe a unique combination of electrical and structural abnormalities associated with a novel SCN5A variant. Our findings broaden the spectrum of cardiac phenotypes associated with SCN5A channelopathy, underlining the complex clinical manifestations of genetic variations within this gene.

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.