Stefan Michael Sattler

BACKGROUND: Horses are one of the few animals that spontaneously develop atrial fibrillation (AF), making them a powerful model for studying AF mechanisms and treatment effects. Despite the initial effectiveness of treatment in horses and humans, AF-induced atrial remodeling compromises its long-term success. Observational studies have suggested that metformin may reduce the risk of AF, but its effects on progressive AF-induced atrial remodeling have yet to be evaluated in a high-fidelity large animal model. METHODS: Here, we used a longitudinal horse model of tachypacing-induced self-sustained AF to characterize the electrical, molecular, and metabolic atrial changes over 4 months of disease, with and without metformin treatment (30 mg/kg orally, twice daily; initiated before AF induction, N=24 horses). Electrophysiological and multiomic approaches were combined with histology, echocardiography, biochemical, and mitochondrial analyses to evaluate disease progression and treatment response. RESULTS: The horse model replicated critical aspects of AF-induced atrial remodeling observed in Humans, including electrical and structural changes. Despite upregulation of metabolic genes and proteins in AF, no significant ultrastructural mitochondrial changes were detected. Metformin plasma trough levels confirmed stable therapeutic exposure. Metformin-treated horses were protected against early AF stabilization and sustained a less complex AF substrate in the right atrium after 4 months of disease. These protective effects were associated with increased right atrial activity of the metabolic regulator, AMPK (AMP-activated protein kinase), changes in metabolic pathways, and modulation of ion-channel gene expression. CONCLUSIONS: Metformin treatment conferred protection against early AF stabilization and selectively attenuated right atrial substrate complexity in a translationally relevant preclinical model. These findings support metformin as a lead molecule for AF prevention, warranting further mechanistic and clinical studies.

Aims: Pulmonary vein isolation (PVI) is the corner stone of modern rhythm control strategies in patients with atrial fibrillation (AF). Sleep-disordered breathing (SDB) is prevalent in more than 50% of patients undergoing AF ablation, and studies have indicated a greater recurrence rate after PVI in patients with SDB. Herein, we study the effect of catheter-based PVI on AF in a pig model for SDB. Methods and results: In 11 sedated spontaneously breathing pigs, obstructive apnoeas were simulated by 75 s of intermittent negative upper airway pressure (INAP) applied by a negative pressure device connected to the endotracheal tube. Intermittent negative upper airway pressures were performed before and after PVI. AF-inducibility and atrial effective refractory periods (aERPs) were determined before and during INAP by programmed atrial stimulation. Pulmonary vein isolation prolonged the aERP by 48 ± 27 ms in the right atrium (RA) (P < 0.0001) and by 40 ± 34 ms in the left atrium (LA) (P = 0.0004). Following PVI, AF-inducibility dropped from 28 ± 26% to 0% (P = 0.0009). Intermittent negative upper airway pressure was associated with a transient aERP-shortening (ΔaERP) in both atria, which was not prevented by PVI (INAP indued ΔaERP after PVI in the RA: −57 ± 34 ms, P = 0.0002; in the LA: −42 ± 24 ms, P < 0.0001). Intermittent negative upper airway pressure was associated with a transient increase in AF-inducibility (from 28 ± 26% to 69 ± 21%; P = 0.0008), which was not attenuated by PVI [INAP-associated AF-inducibility after PVI: 58 ± 33% (P = 0.5)]. Conclusion: Transient atrial arrhythmogenic changes related to acute obstructive respiratory events are not prevented by electrical isolation of the pulmonary veins, which partially explains the increased AF recurrence in patients with SDB after PVI procedures.

During acute myocardial infarction (AMI), the ischemia and necrosis of the infarcted tissue result in local electrophysiological changes, which bring about deviations of the ST segment and T wave. In this case report, the aim was to investigate whether these changes could be detected with a 12-lead electrocardiogram (ECG) during acute occlusion of the coronary artery in a 15-year-old Standardbred mare (scheduled for euthanasia due to non-cardiac health problems). The left anterior descending (LAD) coronary artery was occluded using an angioplasty balloon catheter guided through the carotid artery. Two coronary occlusions of 30 min were induced, separated by a 10-min reperfusion phase. AMI led to ST deviations and T-wave amplitude changes (maximum ST deviation was 1.98 mV; T-wave amplitude increased from 6.58 to 9.25 mV). The ST segment almost returned to the baseline during the reperfusion phase. The ECG changes seen after the infarction were comparable to those reported in other species with AMI, suggesting that the 12-lead-ECG can potentially be used to detect signs of myocardial infarction in horses.

Background and Purpose: Inhibition of the G‐protein gated ACh‐activated inward rectifier potassium current, I_K,ACh may be an effective atrial selective treatment strategy for atrial fibrillation (AF). Therefore, the anti‐arrhythmic and electrophysiological properties of a novel putatively potent and highly specific I_K,ACh inhibitor, XAF‐1407 (3‐methyl‐1‐[5‐phenyl‐4‐[4‐(2‐pyrrolidin‐1‐ylethoxymethyl)‐1‐piperidyl]thieno[2,3‐d]pyrimidin‐6‐yl]azetidin‐3‐ol), were characterised for the first time in vitro and investigated in horses with persistent AF.Experimental Approach: The pharmacological ion channel profile of XAF‐1407 was investigated using cell lines expressing relevant ion channels. In addition, eleven horses were implanted with implantable cardioverter defibrillators enabling atrial tachypacing into self‐sustained AF. The electrophysiological effects of XAF‐1407 were investigated after serial cardioversions over a period of 1 month. Cardioversion success, drug‐induced changes of atrial tissue refractoriness, and ventricular electrophysiology were assessed at baseline (day 0) and days 3, 5, 11, 17, and 29 after AF induction.Key Results: XAF‐1407 potently and selectively inhibited K_ir3.1/3.4 and K_ir3.4/3.4, underlying the I_K,ACh current. XAF‐1407 treatment in horses prolonged atrial effective refractory period as well as decreased atrial fibrillatory rate significantly (~20%) and successfully cardioverted AF, although with a decreasing efficacy over time. XAF‐1407 shortened atrioventricular‐nodal refractoriness, without effect on QRS duration. QTc prolongation (4%) within 15 min of drug infusion was observed, however, without any evidence of ventricular arrhythmia.Conclusion and Implications: XAF‐1407 efficiently cardioverted sustained tachypacing‐induced AF of short duration in horses without notable side effects. This supports I_K,ACh inhibition as a potentially safe treatment of paroxysmal AF in horses, suggesting potential clinical value for other species including humans.

Background: Impact of telemedicine with remote patient monitoring (RPM) in implantable cardioverter–defibrillator (ICD) patients on clinical outcomes has been investigated in various clinical settings with divergent results. However, role of RPM on patient-reported-outcomes (PRO) is unclear. The INFRARED-ICD trial aimed to investigate the effect of RPM in addition to standard-of-care on PRO in a mixed ICD patient cohort. Methods and results: Patients were randomized to RPM (n = 92) or standard in-office-FU (n = 88) serving as control group (CTL). At baseline and on a monthly basis over 1 year, study participants completed the EQ-5D questionnaire for the primary outcome Quality of Life (QoL), the Hospital Anxiety and Depression Scale, and the Florida Patient Acceptance Survey questionnaire for secondary outcomes. Demographic characteristics (82% men, mean age 62.3 years) and PRO at baseline were not different between RPM and CTL. Primary outcome analysis showed that additional RPM was not superior to CTL with respect to QoL over 12 months [+ 1.2 vs. + 3.9 points in CTL and RPM group, respectively (p = 0.24)]. Pre-specified analyses could not identify subgroups with improved QoL by the use of RPM. Neither levels of anxiety (− 0.4 vs. − 0.3, p = 0.88), depression (+ 0.3 vs. ± 0.0, p = 0.38), nor device acceptance (+ 1.1 vs. + 1.6, p = 0.20) were influenced by additional use of RPM. Conclusion: The results of the present study show that PRO were not improved by RPM in addition to standard-of-care FU. Careful evaluation and planning of future trials in selected ICD patients are warranted before implementing RPM in routine practice. Graphic

Background: Inhibition of K_Ca2 channels, conducting I_KCa, can convert atrial fibrillation (AF) to sinus rhythm and protect against its induction. I_KCa inhibition has been shown to possess functional atrial selectivity with minor effects on ventricles. Under pathophysiological conditions with ventricular remodeling, however, inhibiting I_KCa can exhibit both proarrhythmic and antiarrhythmic ventricular effects. The aim of this study was to evaluate the effects of the I_KCa inhibitor AP14145, when given before or after the I_Kr blocker dofetilide, on cardiac function and ventricular proarrhythmia markers in pigs with or without left ventricular dysfunction (LVD). Methods: Landrace pigs were randomized into an AF group (n = 6) and two control groups: SHAM1 (n = 8) and SHAM2 (n = 4). AF pigs were atrially tachypaced (A-TP) for 43 ± 4 days until sustained AF and LVD developed. A-TP and SHAM1 pigs received 20 mg/kg AP14145 followed by 100 µg/kg dofetilide whereas SHAM2 pigs received the same drugs in the opposite order. Proarrhythmic markers such as short-term variability of QT (STV_QT) and RR (STV_RR) intervals, and the number of premature ventricular complexes (PVCs) were measured at baseline and after administration of drugs. The influence on cardiac function was assessed by measuring cardiac output, stroke volume, and relevant echocardiographic parameters. Results: I_KCa inhibition by AP14145 did not increase STV_QT or STV_RR in any of the pigs. I_Kr inhibition by dofetilide markedly increased STV_QT in the A-TP pigs, but not in SHAM operated pigs. Upon infusion of AP14145 the number of PVCs decreased or remained unchanged both when AP14145 was infused after baseline and after dofetilide. Conversely, the number of PVCs increased or remained unchanged upon dofetilide infusion. Neither AP14145 nor dofetilide affected relevant echocardiographic parameters, cardiac output, or stroke volume in any of the groups. Conclusion: I_KCa inhibition with AP14145 was not proarrhythmic in healthy pigs, or in the presence of LVD resulting from A-TP. In pigs already challenged with 100 µg/kg dofetilide there were no signs of proarrhythmia when 20 mg/kg AP14145 were infused. K_Ca2 channel inhibition did not affect cardiac function, implying that K_Ca2 inhibitors can be administered safely also in the presence of LV dysfunction.

Background: Atrial fibrillation (AF) is characterized by electrical and structural remodeling. Irregular and/or fast atrio-ventricular (AV) conduction during AF can result in AV dyssynchrony, tachymyopathy, pressure and volume overload with subsequent dilatation, valve regurgitation, and ventricular dysfunction with progression to heart failure. Objective: To gain further insight into the myocardial pathophysiological changes induced by right atrial tachypacing (A-TP) in a large animal model. Methods: A total of 28 Landrace pigs were randomized as 14 into AF-induced A-TP group and 14 pigs to control group. AF pigs were tachypaced for 43 ± 4 days until in sustained AF. Functional remodeling was investigated by echocardiography (after cardioversion to sinus rhythm). Structural remodeling was quantified by histological preparations with picrosirius red and immunohistochemical stainings. Results: A-TP resulted in decreased left ventricular ejection fraction (LVEF) accompanied by increased end-diastolic and end-systolic left atrium (LA) volume and area. In addition, A-TP was associated with mitral valve (MV) regurgitation, diastolic dysfunction and increased atrial and ventricular fibrotic extracellular matrix (ECM). Conclusions: A-TP induced AF with concomitant LV systolic and diastolic dysfunction, increased LA volume and area, and atrial and ventricular fibrosis.