Molecular basis and proarrhythmic role of enhanced small conductance Ca2+ activated K+ channels in patients with atrial fibrillation

• Applicant: Professor Dr. Dobromir Dobrev
• Subject Area: Pharmacology ; Cardiology, Angiology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 349202494

• Final Report Year: 2023

Final Report Abstract

There remains a significant unmet clinical need for novel safer, more effective antiarrhythmic drugs. Small-conductance Ca2+-activated K+ (SK)-channels show a predominant atrial expression in humans, making them interesting candidates for pharmacological rhythm control of atrial fibrillation (AF). SK-channel inhibitors have significant antiarrhythmic effects in AF animal models, but regulation of SK-channels in AF-patients is poorly understood. Here, we identified a significant upregulation of ISK in atrial cardiomyocytes from cAF-patients and detailed the underlying molecular mechanisms. We provide the first demonstration of AF-associated PP2A upregulation, calmodulin Thr80-dephosphorylation, and PP2A-mediated ISK regulation in human atrial cardiomyocytes. Furthermore, we establish trafficking-dependent upregulation of SK-channel membrane targeting in AF patients as a second factor promoting increased ISK. We present an improved human atrial cardiomyocyte computational model and together with experimental action-potential recordings demonstrate the importance of ISK upregulation for shortening of the atrial effective refractory period. Finally, we revealed a rapid upregulation of plasmalemmal SK2-membrane targeting and ISK after 10 minutes of atrial tachycardia, which is also sensitive to inhibition of PP2A and trafficking pathways. Together, our findings position SK-channels as potentially important contributors to self-promotion of AF in humans, provide novel insight into the molecular control of ISK and provide a mechanistic rationale for the development of SK-channel inhibitors for rhythm control of AF.

Publications

• Calcium Signaling and Cardiac Arrhythmias. Circulation Research, 120(12), 1969-1993.
  Landstrom, Andrew P.; Dobrev, Dobromir & Wehrens, Xander H.T.
  
• Inhibition of Small-Conductance Ca 2+ -Activated K + Channels. Circulation: Arrhythmia and Electrophysiology, 10(10).
  Heijman, Jordi & Dobrev, Dobromir
  
• Regulation of small-conductance potassium channels in patients with atrial fibrillation. In: "Arrhythmia". European Section Meeting of the International Academy of Cardiovascular Sciences, 28-30 Sepermber 2017, Szeged, Hungary.
  Dobrev D.
  
• Antiarrhythmic drugs for atrial fibrillation: Imminent impulses are emerging. IJC Heart & Vasculature, 21, 11-15.
  Dan, Gheorghe-Andrei & Dobrev, Dobromir
  
• Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation. Circulation, 138(20), 2227-2242.
  Yao, Chunxia; Veleva, Tina; Scott, Larry; Cao, Shuyi; Li, Luge; Chen, Gong; Jeyabal, Prince; Pan, Xiaolu; Alsina, Katherina M.; Abu-Taha, Issam; Ghezelbash, Shokoufeh; Reynolds, Corey L.; Shen, Ying H.; LeMaire, Scott A.; Schmitz, Wilhelm; Müller, Frank U.; El-Armouche, Ali; Tony, Eissa N.; Beeton, Christine ... & Li, Na
  
• Mouse Models of Cardiac Arrhythmias. Circulation Research, 123(3), 332-334.
  Dobrev, Dobromir & Wehrens, Xander H.T.
  
• Proarrhythmic Subcellular Signaling in Atrial Fibrillation: Role of Calcium Dependent Potassium Channels. 23rd World Congress on Heart Disease, International Academy of Cardiology, July 27-29, 2018, Boston, USA.
  Dobrev D.
  
• Profibrotic, Electrical, and Calcium-Handling Remodeling of the Atria in Heart Failure Patients With and Without Atrial Fibrillation. Frontiers in Physiology, 9.
  Molina, Cristina E.; Abu-Taha, Issam H.; Wang, Qiongling; Roselló-Díez, Elena; Kamler, Marcus; Nattel, Stanley; Ravens, Ursula; Wehrens, Xander H. T.; Hove-Madsen, Leif; Heijman, Jordi & Dobrev, Dobromir
  
• Regulation of calcium-activated potassium channels in atrial cardiomyocytes. 3rd German Pharm-Tox Summit - 84th Annual Meeting of the German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT), 26 February - 1 March 2018, Göttingen, Germany.
  Dobrev D.
  
• Translational Challenges in Atrial Fibrillation. Circulation Research, 122(5), 752-773.
  Heijman, Jordi; Guichard, Jean-Baptiste; Dobrev, Dobromir & Nattel, Stanley
  
• Postoperative atrial fibrillation: mechanisms, manifestations and management. Nature Reviews Cardiology, 16(7), 417-436.
  Dobrev, Dobromir; Aguilar, Martin; Heijman, Jordi; Guichard, Jean-Baptiste & Nattel, Stanley
  
• Role of inflammatory signaling in atrial fibrillation. International Journal of Cardiology, 287, 195-200.
  Scott, Larry; Li, Na & Dobrev, Dobromir
  
• Trafficking-based strategy to treat atrial fibrillation: Role of SK-channels. In: ”Translating new pharmacology science into clinical practice”. Annual Congress of the European Society of Cardiology, Paris, France.
  Dobrev D.
  
• Atrial Myocyte NLRP3/CaMKII Nexus Forms a Substrate for Postoperative Atrial Fibrillation. Circulation Research, 127(8), 1036-1055.
  Heijman, Jordi; Muna, Azinwi Phina; Veleva, Tina; Molina, Cristina E.; Sutanto, Henry; Tekook, Marcel; Wang, Qiongling; Abu-Taha, Issam H.; Gorka, Marcel; Künzel, Stephan; El-Armouche, Ali; Reichenspurner, Hermann; Kamler, Markus; Nikolaev, Viacheslav; Ravens, Ursula; Li, Na; Nattel, Stanley; Wehrens, Xander H.T. & Dobrev, Dobromir
  
• Molecular Basis of Atrial Fibrillation Pathophysiology and Therapy. Circulation Research, 127(1), 51-72.
  Nattel, Stanley; Heijman, Jordi; Zhou, Liping & Dobrev, Dobromir
  
• Thrombin receptor PAR4 drives canonical NLRP3 inflammasome signaling in the heart. Basic Research in Cardiology, 115(2).
  Fender, Anke C.; Kleeschulte, Sonja; Stolte, Svenja; Leineweber, Katja; Kamler, Markus; Bode, Johannes; Li, Na & Dobrev, Dobromir
  
• Gut microbiota, dysbiosis and atrial fibrillation. Arrhythmogenic mechanisms and potential clinical implications. Cardiovascular Research, 118(11), 2415-2427.
  Gawałko, Monika; Agbaedeng, Thomas A.; Saljic, Arnela; Müller, Dominik N.; Wilck, Nicola; Schnabel, Renate; Penders, John; Rienstra, Michiel; van Gelder, Isabelle; Jespersen, Thomas; Schotten, Ulrich; Crijns, Harry J. G. M.; Kalman, Jonathan M.; Sanders, Prashanthan; Nattel, Stanley; Dobrev, Dobromir & Linz, Dominik
  
• NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmias. Cardiovascular Research, 117(7), 1746-1759.
  Scott, Jr Larry; Fender, Anke C.; Saljic, Arnela; Li, Luge; Chen, Xiaohui; Wang, Xiaolei; Linz, Dominik; Lang, Jilu; Hohl, Mathias; Twomey, Darragh; Pham, Thuy T.; Diaz-Lankenau, Rodrigo; Chelu, Mihail G.; Kamler, Markus; Entman, Mark L.; Taffet, George E.; Sanders, Prashanthan; Dobrev, Dobromir & Li, Na
  
• Stretching the limits of antiarrhythmic drug therapy: The promise of small-conductance calcium-activated potassium channel blockers. IJC Heart & Vasculature, 37, 100924.
  Heijman, Jordi; Rahm, Ann-Kathrin & Dobrev, Dobromir
  
• The crosstalk between cardiomyocyte calcium and inflammasome signaling pathways in atrial fibrillation. Pflügers Archiv - European Journal of Physiology, 473(3), 389-405.
  Wang, Xiaolei; Chen, Xiaohui; Dobrev, Dobromir & Li, Na
  
• Why translation from basic discoveries to clinical applications is so difficult for atrial fibrillation and possible approaches to improving it. Cardiovascular Research, 117(7), 1616-1631.
  Nattel, Stanley; Sager, Philip T.; Hüser, Jörg; Heijman, Jordi & Dobrev, Dobromir
  
• Adiposity-associated atrial fibrillation: molecular determinants, mechanisms, and clinical significance. Cardiovascular Research, 119(3), 614-630.
  Gawałko, Monika; Saljic, Arnela; Li, Na; Abu-Taha, Issam; Jespersen, Thomas; Linz, Dominik; Nattel, Stanley; Heijman, Jordi; Fender, Anke & Dobrev, Dobromir
  
• Emerging Antiarrhythmic Drugs for Atrial Fibrillation. International Journal of Molecular Sciences, 23(8), 4096.
  Saljic, Arnela; Heijman, Jordi & Dobrev, Dobromir
  
• Inflammatory signalling in atrial cardiomyocytes: a novel unifying principle in atrial fibrillation pathophysiology. Nature Reviews Cardiology, 20(3), 145-167.
  Dobrev, Dobromir; Heijman, Jordi; Hiram, Roddy; Li, Na & Nattel, Stanley
  
• Molecular determinants and therapeutic potential of focal ectopic activity: more than meets the Iti. European Heart Journal, 43(40), 4208-4210.
  Heijman, Jordi & Dobrev, Dobromir