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Atrial fibrillation (AF) is the most common arrhythmia and is associated with increased morbidity and mortality. The mechanisms underlying the transition from paroxysmal to persistent AF are still a matter of debate. Recent studies indicate a potential role for metabolic remodelling in the AF stabilization process and increased levels of a specific metabolic substrate, succinate, have been found in blood plasma of AF patients. While succinate is known to increase reactive oxygen species (ROS) production, the role of the succinate receptor (GPR91) in atrial function is unknown. To assess the impact of the succinate pathway on AF vulnerability in a sheep model. GPR91 expression levels were quantified by Western Blot (WB) in a previously described sheep model of persistent AF induced by burst-pacing. Optical experiments were subsequently performed in ex vivo right atria (RA) from control sheep (n = 5). RA were perfused by Tyrode solution, then supplemented with the cis-epoxysuccinic acid (cESA), a specific activator of GPR91 (150 μM) to study its involvement in atrial electrophysiology and AF. Action potential duration at 80% of repolarization (APD80) were assessed from 2 to 5 Hz pacing frequency. We used an S1S2 pacing protocol to determine effective refractory period (ERP) and a burst pacing protocol (30 Hz) to assess ex vivo AF vulnerability. Finally, we investigated these properties in a human RA from an AF patient. WB experiments revealed an increase in GPR91 expression in AF sheep compared to sham sheep. Interestingly, in resistant sheep (no AF after 90 days of burst pacing), expression levels were decreased compared to sham. During cESA perfusion in control sheep RA, sinus rhythm (119 vs. 95 bpm; P = 0.03) and ERP (202 vs. 178 ms; P = 0.36) were decreased when compared to baseline. We also observed a decrease in APD80 (199 vs. 177 ms; P = 0.009) and in CV (127 vs. 115 cm/sec; P = 0.01). These electrophysiological perturbations led to an increase in AF vulnerability by burst pacing (0% vs. 60%) and an increase in spontaneous arrhythmias. These results were corroborated in the human RA were cESA decreased APD80 (265 vs. 241 ms), ERP (240 vs. 220 ms), and CV (119 vs. 94 cm/sec) and increased arrhythmia vulnerability. For the first time, we demonstrated that GPR91 is expressed in atrial tissue and that its activation through succinate can play a major role in AF mechanisms. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most sustained arrhythmia and increases morbidity and mortality. However, development and maintenance of AF is a still poorly understood process. Metabolic remodelling could induce transition from paroxysmal to persistent AF. Succinate levels are increased in AF patients indicating a potential role for metabolic remodelling. To assess the impact of the succinate pathway on the electrophysiological properties of right atria (RA) in persistent AF sheep model. Optical experiments were performed in ex vivo RA from a burst pacing AF sheep model. RA were perfused by Tyrode solution with glucose (5.6 mM), subsequently replaced by succinate (10 mM) to increase mitochondrial reactive oxygen species (ROS) production which are known to modulate excitation-contraction coupling (ECC) and study metabolic remodelling. An activator of the succinate β-adrenergic receptor (GPR91), cis-epoxysuccinic acid (300 μM), was used to study the GPR91 involvement in atrial electrophysiology and AF. Action potential duration at 80% of repolarization (APD80) were assessed from 2 to 5 Hz pacing frequency and during sinus rhythm (SR). We used an S1S2 pacing protocol to determine effective refractory period (ERP) and a burst pacing protocol (30 Hz) to assess ex vivo AF vulnerability. Finally, an organ donation program allowed us to investigate these properties in a human RA from an AF patient. During succinate perfusion SR is decreased in Sham (1,5 vs 1,2 Hz; P = 0,03), AF (1,5 vs 1 Hz; P = 0,003) and resistant (1,3 vs 1 Hz; P = 0,01) sheep, ERP is increased in AF sheep (184 vs 344 ms; P = 0,0007) and APD80 is increased in Sham (217 vs 264 ms; P = 0,0004) and AF sheep (195 vs 275 ms; P = 0,003). We also observed an increase in amplitude alternans which can induce re-entries and therefore be pro-arrhythmic. These results seems to be confirmed on human AF RA by increasing APD80 (257 vs 309 ms), ERP (260 vs 330 ms) and spontaneous arrhythmias. GPR91 activation led to a slowing of SR (1,7 vs 1,3 Hz; P = 0,03), a shortening of APD80 (200 vs 170 ms; P = 0,007) and an increase in spontaneous arrhythmias. A dysregulation of ECC could explain our results consistently with the ROS involvement and metabolic remodelling in AF. For the first time, we also demonstrated that GPR91 pathway is involved in atrial electrophysiology and could be involved in AF mechanisms. [ABSTRACT FROM AUTHOR]

Background: Changes in mitochondria have been implicated in atrial fibrillation (AF), but their manifestations and significance are poorly understood. Here, we studied changes in mitochondrial morphology and function during AF and assessed the effect of a mitochondrial-targeted intervention in a large animal model., Methods and Results: Atrial cardiomyocytes (ACMs) were isolated from dogs in electrically-driven AF for periods of 24 hours to 3 weeks and from humans with/without longstanding persistent AF. Mitochondrial Ca 2+ -concentration ([Ca 2+ ] Mito ), reactive oxygen species (mtROS) production, membrane potential (ΔΨ m ), permeability transition-pore (mPTP) opening and flavin adenine dinucleotide (FAD) were measured via confocal microscopy; nicotine adenine dinucleotide (NADH) under ultraviolet light. mtROS-production increased within 24 hours and superoxide-dismutase type-2 was significantly reduced from 3-day AF. [Ca 2+ ] Mito and mPTP-opening frequency/duration increased progressively during AF. Mitochondrial depolarization was detectable 24 hours after AF-onset. NADH increased by 15% at 24-hour AF, concomitant with increased pyruvate-dehydrogenase expression, then gradually decreased. Mitochondria enlarged and elongated at 24-hour and 3-day AF, followed by progressive fragmentation, rupture and shrinkage. Mitochondrial fusion protein-1 (MFN1) was reduced from 3-day to 3-week AF and phosphorylated dynamin-related protein-1 (p-DRP1ser-616) increased after 1 week of canine AF and in human AF. Addition of the mitochondrial antioxidant MitoTempo attenuated action-potential shortening and L-type Ca 2+ -current (I CaL )-downregulation in canine and human AF ACMs in vitro . Administration of the orally-active mitochondrial-targeted ubiquinone mitoquinone to dogs during 3-week AF prevented mitochondrial Ca 2+ -overload, mtROS-overproduction, structural damage and abnormalities in ΔΨ m and respiration. Functionally, mitoquinone reduced AF-induced Ca 2+ -current downregulation, action-potential abbreviation, contractile dysfunction and fibrosis, preventing AF-substrate development and AF-sustainability., Conclusions: Mitochondria show a series of changes during AF, with early hyperfunction and enhanced ROS-generation, followed by progressive damage and dysfunction. Mitochondrial-targeted therapy prevents mitochondrial dysfunction and attenuates adverse AF-related remodeling, positioning mitochondrial protection as a potential novel therapeutic target in AF.

Background and Purpose: Pulmonary hypertension (PH) is a cardiovascular disease characterised by an increase in pulmonary arterial (PA) resistance leading to right ventricular (RV) failure. Reactive oxygen species (ROS) play a major role in PH. OP2113 is a drug with beneficial effects on cardiac injuries that targets mitochondrial ROS. The aim of the study was to address the in vivo therapeutic effect of OP2113 in PH., Experimental Approach: PH was induced by 3 weeks of chronic hypoxia (CH-PH) in rats treated with OP2113 or its vehicle via subcutaneous osmotic mini-pumps. Haemodynamic parameters and both PA and heart remodelling were assessed. Reactivity was quantified in PA rings and in RV or left ventricular (LV) cardiomyocytes. Oxidative stress was detected by electron paramagnetic resonance and western blotting. Mitochondrial mass and respiration were measured by western blotting and oxygraphy, respectively., Key Results: In CH-PH rats, OP2113 reduced the mean PA pressure, PA remodelling, PA hyperreactivity in response to 5-HT, the contraction slowdown in RV and LV and increased the mitochondrial mass in RV. Interestingly, OP2113 had no effect on haemodynamic parameters, both PA and RV wall thickness and PA reactivity, in control rats. Whereas oxidative stress was evidenced by an increase in protein carbonylation in CH-PH, this was not affected by OP2113., Conclusion and Implications: Our study provides evidence for a selective protective effect of OP2113 in vivo on alterations in both PA and RV from CH-PH rats without side effects in control rats., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Cardiac alternans has been associated with an increased propensity to lethal tachyarrhythmias such as ventricular tachycardia and fibrillation (VT/VF). Myocardial infarction (MI), resulting from restricted oxygen supply to the heart, is a known substrate for VT/VF. Here, we investigate the utility of cardiac alternans as a predictor of tachyarrhythmias in a chronic MI ovine model. In-vivo electrophysiological studies were performed to assess the change in microvolt T-wave alternans (TWA) with induction of acute ischemia following coronary artery occlusion. 24-hour telemetry was performed in an ambulatory animal for 6 weeks to monitor the progression of TWA with chronic MI. At 6 weeks, ex-vivo optical mapping experiments were performed to assess the spatiotemporal evolution of alternans in sham (n=5) and chronic MI hearts (n=8). Our results demonstrate that chronic MI leads to significant electrophysiological changes in the cardiac substrate. Significant increase in TWA is observed post occlusion and a steady rise in alternans is seen with progression of chronic MI. Compared to sham, chronic MI hearts show significant presence of localized action potential amplitude alternans, which spatially evolve with an increase in pacing frequency. Clinical Relevance - Our results demonstrate that localized alternans underlie arrhythmogenesis in chronic MI hearts and microvolt TWA can serve as a biomarker of disease progression during chronic MI.