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- Cellular and Molecular Mechanisms of Atrial Arrhythmogenesis in Patients With Paroxysmal Atrial Fibrillation
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Cellular and Molecular Mechanisms of Atrial Arrhythmogenesis in Patients With Paroxysmal Atrial Fibrillation
Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. There is substantial information available about cellular electrophysiological abnormalities in patients with long-standing persistent AF, but the atrial-cellular pathophysiology in patients with paroxysmal AF (pAF) is largely unknown. Here, we used simultaneous measurements of intracellular [Ca2+] and membrane current/potential in atrial cardiomyocytes from sinus rhythm and pAF patients (last AF episode a median of 10–20 days preoperatively), together with biochemistry and computational modeling, to define the cellular and molecular mechanisms promoting atrial arrhythmogenesis in pAF. L-type Ca2+ currents and action potential durations were unaltered in pAF patients, indicating the absence of typical AF-associated remodeling. However, cardiomyocytes from pAF patients had enhanced diastolic sarcoplasmic reticulum (SR) Ca2+ leak and increased susceptibility to spontaneous diastolic SR Ca2+-release events, causing delayed after-depolarizations/triggered activities that promote atrial ectopic (focal) activity. Pharmacological and biochemical studies indicated that the susceptibility to spontaneous cellular activity in pAF was attributable to enhanced SR Ca2+ uptake, resulting from phospholamban hyperphosphorylation (removing phospholamban-induced inhibition of SR uptake), and ryanodine receptor (SR Ca2+ release) channel dysregulation, including enhanced ryanodine receptor expression and increased single-channel open probability. Simulation studies indicated that both increased SR Ca2+ leak and enhanced SR Ca2+ uptake likely contribute to aberrant diastolic SR Ca2+–release events. Our findings constitute the first direct evidence for an important role of Ca2+-dependent ectopic activity in atrial arrhythmogenesis of pAF patients and provide insights into underlying mechanisms. The cellular and molecular mechanisms underlying abnormal Ca2+ handling in pAF are distinct from those of long-standing persistent AF patients, suggesting possible opportunities to develop tailored therapeutic approaches for pAF. See p 145.
Growth Properties of Cardiac Stem Cells Are a Novel Biomarker of Patients’ Outcome After Coronary Bypass Surgery
The efficacy of bypass surgery in improving ventricular function in patients with severe coronary atherosclerosis and ischemic cardiomyopathy cannot be easily predicted. The preoperative conditions may be similar, but the mid- …
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- Cellular and Molecular Mechanisms of Atrial Arrhythmogenesis in Patients With Paroxysmal Atrial Fibrillation
- Growth Properties of Cardiac Stem Cells Are a Novel Biomarker of Patients’ Outcome After Coronary Bypass Surgery
- Outcome Impact of Coronary Revascularization Strategy Reclassification With Fractional Flow Reserve at Time of Diagnostic Angiography: Insights From a Large French Multicenter Fractional Flow Reserve Registry
- Mental Disorders Across the Adult Life Course and Future Coronary Heart Disease: Evidence for General Susceptibility
- Reporting Trends and Outcomes in ST-Segment–Elevation Myocardial Infarction National Hospital Quality Assessment Programs
- Inaccuracy of Estimated Resting Oxygen Uptake in the Clinical Setting
- Pathology of Second-Generation Everolimus-Eluting Stents Versus First-Generation Sirolimus- and Paclitaxel-Eluting Stents in Humans
- Neurological Injury After Neonatal Cardiac Surgery: A Randomized, Controlled Trial of 2 Perfusion Techniques
- Efficacy and Safety of Longer-Term Administration of Evolocumab (AMG 145) in Patients With Hypercholesterolemia: 52-Week Results From the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) Randomized Trial
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