Progress DHF - Mechanisms for the Progression from Diastolic Dysfunction to Diastolic Heart Failure

• Applicant: Professor Lars Maier
• Subject Area: Cardiology, Angiology ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 316914177

Final Report Abstract

We have successfully collaborated in this French-German project and investigated CaMKII-dependent NaV1.5 channel function and described novel phosphorylation sites at this important channel. As suggested by the initial reviewers in 2016 we have focused this highly complex project on these main questions. In addition, we have investigated novel CaMKII inhibitors (RA608, GS-680, and AS105) and their role on NaV1.5 with respect to myocytes function and arrhythmias. All inhibitors seem to work and could be potential therapeutic approaches to treat cardiac dysfunction in heart failure. Moreover, due to the rising importance of SGLT2-inhibitors which alters Na handling in certain cells, Empagliflozin was investigated with respect to its mechanism of action in cardiac myocytes. SGLT2-inhibitors nowadays are not only used for the treatment of diabetes but also for heart failure therapy and improve prognosis in large randomized placebo-controlled trials for patients with heart failure. We found that Empagliflozin directly improves cardiac myocyte function (including diastolic function) and reduces proarrhtyhmogenic events. Due to the recent progress in knowledge about CaMKII-dependent effects on glucose and Na handling, activation on CaMKII was recently investigated with respect to its role in atrial fibrillation in collaboration with Mark Anderson´s group in Baltimore. We could also show in a translational approach in patients with sleep-disordered breathing (SDB) that in atrial myocardium of patients with SDB, increased CaMKII-dependent phosphorylation of NaV1.5 results in dysregulation of INa with proarrhythmic activity that was independent from preexisting comorbidities. We concluded that inhibition of CaMKII may be useful for prevention or treatment of arrhythmias in SDB.

Publications

• C-terminal phosphorylation of NaV1.5 impairs FGF13-dependent regulation of channel inactivation. J Biol Chem. 292:17431-17448.2017
  Burel S, Coyan FC, Lorenzini M, Meyer MR, Lichti CF, Brown JH, Loussouarn G, Charpentier F, Nerbonne JM, Townsend RR, Maier LS, Marionneau C
  
• Empagliflozin directly improves diastolic function in human heart failure. Eur J Heart Fail. 20:1690- 1700.2018
  Pabel S, Wagner S, Bollenberg H, Bengel P, Kovács Á, Schach C, Tirilomis P, Mustroph J, Renner A, Gummert J, Fischer T, Van Linthout S, Tschöpe C, Streckfuss- Bömeke K, Hasenfuss G, Maier LS, Hamdani N, Sossalla S
  
• Empagliflozin reduces Ca/calmodulin-dependent kinase II activity in isolated ventricular cardiomyocytes. ESC Heart Fail. 5:642-648.2018
  Mustroph J, Wagemann O, Lücht CM, Trum M, Hammer KP, Sag CM, Lebek S, Tarnowski D, Reinders J, Perbellini F, Terracciano C, Schmid C, Schopka S, Hilker M, Zausig Y, Pabel S, Sossalla ST, Schweda F, Maier LS, Wagner S
  
• Improvement of Cardiomyocyte Function by a Novel Pyrimidine-Based CaMKII-Inhibitor. J Mol Cell Cardiol. 115:73-81.2018
  Neef S, Steffens A, Pellicena P, Mustroph J, Lebek S, Ort KR, Schulman H, Maier LS
  
• The novel CaMKII inhibitor GS-680 reduces diastolic SR Ca leak and prevents CaMKII-dependent pro-arrhythmic activity. J Mol Cell Cardiol. 118:159-168.2018
  Lebek S, Plößl A, Baier M, Mustroph J, Tarnowski D, Schopka S, Floerchinger B, Schmid C, Zausig Y, Pagratis N, Marchand B, Koltun DO, Hung WK, Ahmadyar S, Belardinelli L, Maier LS, Wagner S
  
• Enhanced CaMKII-Dependent Late INa Induces Atrial Pro-Arrhythmic Activity in Patients with Sleep-Disordered Breathing. Circ Res. 126:603-615.2020
  Lebek S, Pichler K, Reuthner K, Trum M, Tafelmeier M, Mustroph J, Camboni D, Rupprecht L, Schmid C, Maier LS, Arzt M, Wagner S
  
• The oral CaMKII inhibitor RA608 improves contractile function and prevents arrhythmias in heart failure. ESC Heart Fail. 7:2871-2883.2020
  Mustroph J, Drzymalski M, Baier M, Biedermann A, Memmel B, Durczok M, Neef S, Sag CM, Floerchinger B, Rupprecht L, Schmid C, Zausig Y, Bégis G, Briand V, Ozoux ML, Tamarelle D, Ballet V, Janiak P, Beauverger P, Maier LS, Wagner S
  
• Oxidized-CaMKII and O-GlcNAcylation cause increased atrial fibrillation in diabetic mice by distinct mechanisms. J Clin Invest. 131:e95747.2021
  Mesubi OO, Rokita AG, Abrol N, Wu Y, Chen B, Wang Q, Granger JM, Tucker-Bartley A, Luczak ED, Murphy KR, Umapathi P, Banerjee PS, Boronina T, Cole RN, Maier LS, Wehrens XH, Pomerantz JL, Song LS, Ahima R, Hart GW, Zachara NE, Anderson ME
  
• Proteomic and functional mapping of cardiac NaV1.5 channel phosphorylation sites. J Gen Physiol. 153:e202012646.2021
  Lorenzini M, Burel S, Lesage A, Wagner E, Charrière C, Chevillard PM, Evrard B, Maloney D, Ruff KM, Pappu RV, Wagner S, Nerbonne JM, Silva JR, Townsend RR, Maier LS, Marionneau C