Research in intensive care medicine

Catheter-based closure of the left atrial appendage (LAAC) is a potential treatment option for reducing the risk of stroke in patients with atrial fibrillation and a high risk of stroke and haemorrhage. The safety profile of percutaneous implantation has improved in recent years due to the further development of implantation technology and the introduction of new or optimised devices. These observations are the starting point for testing the treatment method for new areas of application, such as atrial fibrillation patients with a low risk of bleeding, atrial fibrillation patients after pulmonary vein isolation or patients after electrical isolation of the left atrial appendage. The therapeutic principle is also supported by new data showing the efficacy of surgical closure of the left atrial appendage in addition to anticoagulation during cardiac surgery.

Current studies: Champion-AF, Option, Closure-AF-DHZK16, Catalyst, OMEGA Registry Lambre Registry

• Comparison of different measurement methods of haemodynamics when using percutaneous support systems (microaxial pump) in daily practice.
• Immunological activation (innate/adaptive immunity) and characterisation of SIRS during percutaneous cardiovascular support.
• Development of a registry for percutaneous cardiovascular support in high-risk PCI and cardiogenic shock (Impella, ECMO, Impella+ECMO).
• Evaluation of prognostic biomarkers after cardiopulmonary resuscitation

1. One-Year Outcomes after PCI Strategies in Cardiogenic Shock. Thiele H, Akin I, Sandri M, de Waha-Thiele S, Meyer-Saraei R, Fuernau G, Eitel I, Nordbeck P, Geisler T, Landmesser U, Skurk C, Fach A, Jobs A, Lapp H, Piek JJ, Noc M, Goslar T, Felix SB, Maier LS, Stepinska J, Oldroyd K, Serpytis P, Montalescot G, Barthelemy O, Huber K, Windecker S, Hunziker L, Savonitto S, Torremante P, Vrints C, Schneider S, Zeymer U, Desch S; CULPRIT-SHOCK Investigators. N Engl J Med. 2018 Nov 1;379(18):1699-1710. doi: 10.1056/NEJMoa1808788.
2. PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock. Thiele H, Akin I, Sandri M, Fuernau G, de Waha S, Meyer-Saraei R, Nordbeck P, Geisler T, Landmesser U, Skurk C, Fach A, Lapp H, Piek JJ, Noc M, Goslar T, Felix SB, Maier LS, Stepinska J, Oldroyd K, Serpytis P, Montalescot G, Barthelemy O, Huber K, Windecker S, Savonitto S, Torremante P, Vrints C, Schneider S, Desch S, Zeymer U; CULPRIT-SHOCK Investigators. N Engl J Med. 2017 Dec 21;377(25):2419-2432. doi: 10.1056/NEJMoa1710261.

1. Extracorporeal Life Support in Infarct-Related Cardiogenic Shock. Thiele H, Zeymer U, Akin I, Behnes M, Rassaf T, Mahabadi AA, Lehmann R, Eitel I, Graf T, Seidler T, Schuster A, Skurk C, Duerschmied D, Clemmensen P, Hennersdorf M, Fichtlscherer S, Voigt I, Seyfarth M, John S, Ewen S, Linke A, Tigges E, Nordbeck P, Bruch L, Jung C, Franz J, Lauten P, Goslar T, Feistritzer HJ, Pöss J, Kirchhof E, Ouarrak T, Schneider S, Desch S, Freund A; ECLS-SHOCK Investigators.  N Engl J Med. 2023 Oct 5;389(14):1286-1297. doi: 10.1056/NEJMoa2307227.

1. Microaxial Flow Pump or Standard Care in Infarct-Related Cardiogenic Shock. Møller JE, Engstrøm T, Jensen LO, Eiskjær H, Mangner N, Polzin A, Schulze PC, Skurk C, Nordbeck P, Clemmensen P, Panoulas V, Zimmer S, Schäfer A, Werner N, Frydland M, Holmvang L, Kjærgaard J, Sørensen R, Lønborg J, Lindholm MG, Udesen NLJ, Junker A, Schmidt H, Terkelsen CJ, Christensen S, Christiansen EH, Linke A, Woitek FJ, Westenfeld R, Möbius-Winkler S, Wachtell K, Ravn HB, Lassen JF, Boesgaard S, Gerke O, Hassager C; DanGer Shock Investigators. N Engl J Med. 2024 Apr 18;390(15):1382-1393. doi: 10.1056/NEJMoa2312572.

1. The ACCOST-HH Trial. Skurk C, Rottbauer W, Kessler M, Akin I, Kluge S, Burdelski C, Blankenberg S, Zeller T, Landmesser U, Karakas M. Eur Heart J. 2020 Dec 1;41(45):4296-4298. doi: 10.1093/eurheartj/ehaa757.
2. Single-dose of adrecizumab versus placebo in acute cardiogenic shock (ACCOST-HH): an investigator-initiated, randomised, double-blinded, placebo-controlled, multicentre trial. Karakas M, Akin I, Burdelski C, Clemmensen P, Grahn H, Jarczak D, Keßler M, Kirchhof P, Landmesser U, Lezius S, Lindner D, Mebazaa A, Nierhaus A, Ocak A, Rottbauer W, Sinning C, Skurk C, Söffker G, Westermann D, Zapf A, Zengin E, Zeller T, Kluge S. Lancet Respir Med. 2022 Mar;10(3):247-254. doi: 10.1016/S2213-2600(21)00439-2.

1. Coronary Angiography After Out-of-Hospital Cardiac Arrest Without ST-Segment Elevation: One-Year Outcomes of a Randomized Clinical Trial. Desch S, Freund A, Akin I, Behnes M, Preusch MR, Zelniker TA, Skurk C, Landmesser U, Graf T, Eitel I, Fuernau G, Haake H, Nordbeck P, Hammer F, Felix SB, Hassager C, Kjærgaard J, Fichtlscherer S, Ledwoch J, Lenk K, Joner M, Steiner S, Liebetrau C, Voigt I, Zeymer U, Brand M, Schmitz R, Horstkotte J, Jacobshagen C, Pöss J, Abdel-Wahab M, Lurz P, Jobs A, de Waha S, Olbrich D, Sandig F, König IR, Brett S, Vens M, Klinge K, Thiele H; TOMAHAWK Investigators. JAMA Cardiol. 2023 Sep 1;8(9):827-834. doi: 10.1001/jamacardio.2023.2264.
2. Angiography after Out-of-Hospital Cardiac Arrest without ST-Segment Elevation. Desch S, Freund A, Akin I, Behnes M, Preusch MR, Zelniker TA, Skurk C, Landmesser U, Graf T, Eitel I, Fuernau G, Haake H, Nordbeck P, Hammer F, Felix SB, Hassager C, Engstrøm T, Fichtlscherer S, Ledwoch J, Lenk K, Joner M, Steiner S, Liebetrau C, Voigt I, Zeymer U, Brand M, Schmitz R, Horstkotte J, Jacobshagen C, Pöss J, Abdel-Wahab M, Lurz P, Jobs A, de Waha-Thiele S, Olbrich D, Sandig F, König IR, Brett S, Vens M, Klinge K, Thiele H; TOMAHAWK Investigators. N Engl J Med. 2021 Dec 30;385(27):2544-2553. doi: 10.1056/NEJMoa2101909.

Im Rahmen der weiteren wissenschaftlichen Aufarbeitung der randomisierten Studien sind die Mitglieder der AG aktiv an Subanalysen der Daten beteiligt.

1. Thevathasan T., Kenny MA., Krause FJ., et al. Left-ventricular Unloading in Extracorporeal Cardiopulmonary Resuscitation due to Acute Myocardial Infarction - A Multicenter Study. Resuscitation 2023:109775
2. Thevathasan T., Füreder L., Fechtner M., et al. Left-Ventricular Unloading With Impella During Refractory Cardiac Arrest Treated With Extracorporeal Cardiopulmonary Resuscitation: A Systematic Review and Meta-Analysis. Crit Care Med 2024
3. Thevathasan T., Gregers E., Rasalingam Mørk S., et al. Lactate and lactate clearance as predictors of one-year survival in extracorporeal cardiopulmonary resuscitation - An international, multicentre cohort study. Resuscitation 2024;198. Doi: 10.1016/J.RESUSCITATION.2024.110149
4. Thevathasan T., Füreder L., Donker DW., et al. Case report: Refractory cardiac arrest supported with veno-arterial-venous extracorporeal membrane oxygenation and left-ventricular Impella CP®–Physiological insights and pitfalls of ECMELLA. Front Cardiovasc Med 2022;9:3220
5. Thevathasan T., Paul J., Gaul AL., et al. Mortality and healthcare resource utilisation after cardiac arrest in the United States - A 10-year nationwide analysis prior to the COVID-19 pandemic. Resuscitation 2023;193
6. Voß F., Thevathasan T., Scholz KH., et al. Accredited cardiac arrest centers facilitate eCPR and improve neurological outcome. Resuscitation 2024;194
7. Left Ventricular Unloading Is Associated With Lower Mortality in Patients With Cardiogenic Shock Treated With Venoarterial Extracorporeal Membrane Oxygenation: Results From an International, Multicenter Cohort Study. Schrage B, Becher PM, Bernhardt A, Bezerra H, Blankenberg S, Brunner S, Colson P, Cudemus Deseda G, Dabboura S, Eckner D, Eden M, Eitel I, Frank D, Frey N, Funamoto M, Goßling A, Graf T, Hagl C, Kirchhof P, Kupka D, Landmesser U, Lipinski J, Lopes M, Majunke N, Maniuc O, McGrath D, Möbius-Winkler S, Morrow DA, Mourad M, Noel C, Nordbeck P, Orban M, Pappalardo F, Patel SM, Pauschinger M, Pazzanese V, Reichenspurner H, Sandri M, Schulze PC, H G Schwinger R, Sinning JM, Aksoy A, Skurk C, Szczanowicz L, Thiele H, Tietz F, Varshney A, Wechsler L, Westermann D. Circulation. 2020 Dec;142(22):2095-2106. doi: 10.1161/CIRCULATIONAHA.120.048792.

1. Impella Support for Acute Myocardial Infarction Complicated by Cardiogenic Shock. Schrage B, Ibrahim K, Loehn T, Werner N, Sinning JM, Pappalardo F, Pieri M, Skurk C, Lauten A, Landmesser U, Westenfeld R, Horn P, Pauschinger M, Eckner D, Twerenbold R, Nordbeck P, Salinger T, Abel P, Empen K, Busch MC, Felix SB, Sieweke JT, Møller JE, Pareek N, Hill J, MacCarthy P, Bergmann MW, Henriques JPS, Möbius-Winkler S, Schulze PC, Ouarrak T, Zeymer U, Schneider S, Blankenberg S, Thiele H, Schäfer A, Westermann D. Circulation. 2019 Mar 5;139(10):1249-1258. doi: 10.1161/CIRCULATIONAHA.118.036614.

The interaction of the innate and adaptive immune response with cardiac cells is investigated in the working group at the molecular level in various diseases, including animal models, and confirmed by studies in humans. To this end, the Skurk research group has maintained a successful collaboration with the research group of Prof Carmen Scheibenbogen (Institute of Medical Immunology Charité/BCRT) for many years.

Effects of Foxo3a on immunomodulation and cardiac remodelling (DFG SK 271/3-1):

In further work we identified the forkhead transcription factor FOXO3a as a master - regulator of APN expression during cardiovascular inflammatory processes. So far, little is known about the effects of this evolutionarily conserved transcription factor on cardiac pathologies. We could show that Foxo3a inhibits the hypertrophic response in cardiac myocytes and preliminary data indicate an influence of Foxo3a in cardiac remodelling and redox detoxification. Furthermore, we investigate Foxo3a with regard to its regulatory role in the innate and adaptive immune response. The characterisation of FOXO3a function in the cardiovascular inflammatory response as well as in cardiac remodelling processes is investigated in this project. Effects of modulation of FOXO3a activity will be studied in vitro in immune and cardiac cells as well as in various in vivo mouse models of cardiac inflammation and injury. In patients with cardiomyopathy, acute myocardial infarction or allograft rejection after heart transplantation, FOXO3a expression/activation status as well as the influence of FOXO3a polymorphisms will be correlated with immunogenic and outcome parameters. Finally, the effects of therapeutic modulation of FOXO3a on the immune response as well as on cardiac function and remodelling will be investigated in animal models. Since modulators of FOXO3a function are currently being developed in oncology, this approach has a high potential for clinical translation in cardiovascular diseases to inhibit inflammatory processes and remodelling.

1. The Akt-regulated forkhead transcription factor FOXO3a controls endothelial cell viability through modulation of the caspase-8 inhibitor FLIP. Skurk C, Maatz H, Kim HS, Yang J, Abid MR, Aird WC, Walsh K. J Biol Chem. 2004 Jan 9;279(2):1513-25. doi: 10.1074/jbc.M304736200
    
2. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL. Cell. 2004 Apr 30;117(3):399-412. doi: 10.1016/s0092-8674(04)00400-3.
    
3. The FOXO3a transcription factor regulates cardiac myocyte size downstream of AKT signaling. Skurk C, Izumiya Y, Maatz H, Razeghi P, Shiojima I, Sandri M, Sato K, Zeng L, Schiekofer S, Pimentel D, Lecker S, Taegtmeyer H, Goldberg AL, Walsh K. J Biol Chem. 2005 May 27;280(21):20814-23. doi: 10.1074/jbc.M500528200.
    
4. Akt/FOXO3a signaling modulates the endothelial stress response through regulation of heat shock protein 70 expression. Kim HS, Skurk C, Maatz H, Shiojima I, Ivashchenko Y, Yoon SW, Park YB, Walsh K. FASEB J. 2005 Jun;19(8):1042-4. doi: 10.1096/fj.04-2841fje.
    
5. The forkhead transcription factor Foxo3 negatively regulates natural killer cell function and viral clearance in myocarditis. Loebel M, Holzhauser L, Hartwig JA, Shukla PC, Savvatis K, Jenke A, Gast M, Escher F, Becker SC, Bauer S, Stroux A, Beling A, Kespohl M, Pinkert S, Fechner H, Kuehl U, Lassner D, Poller W, Schultheiss HP, Zeller T, Blankenberg S, Papageorgiou AP, Heymans S, Landmesser U, Scheibenbogen C, Skurk C. Eur Heart J. 2018 Mar 7;39(10):876-887. doi: 10.1093/eurheartj/ehx624.
    
6. Metformin Attenuates ROS via FOXO3 Activation in Immune Cells. Hartwig J, Loebel M, Steiner S, Bauer S, Karadeniz Z, Roeger C, Skurk C, Scheibenbogen C, Sotzny F. Front Immunol. 2021 Apr 19;12:581799. doi: 10.3389/fimmu.2021.581799. eCollection 2021.
    
7. FOXO3A acts as immune response modulator in human virus-negative inflammatory cardiomyopathy. Makrutzki-Zlotek K, Escher F, Karadeniz Z, Aleshcheva G, Pietsch H, Küchler K, Schultheiss HP, Heidecker B, Poller W, Landmesser U, Scheibenbogen C, Thevathasan T, Skurk C. Heart. 2023 May 15;109(11):846-856. doi: 10.1136/heartjnl-2022-321732.