Abstract
Altered Ca2+ handling in cardiomyocytes can lead to arrhythmias in the rare, inherited disorder catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1), and in the early reperfusion phase following a myocardial infarction (MI). In CPVT1 Ca2+ leak from the sarcoplasmic reticulum occurs due to gain-of-function mutations in the cardiac Ryanodine receptor (RyR2), and targeting the upstream regulatory protein Ca2+/calmodulin-dependent protein kinase II (CaMKII), has been suggested as a potential therapeutic target. However, it is not known whether such interventions could lead to a separate arrhythmia mechanism, called Ca2+ alternans instead. In the reperfusion phase following MI, the return of oxygenated blood leads to acidosis, increased oxidative stress and Ca2+ overload in the heart. This may cause Ca2+ leak through RyR2, and be arrhythmogenic. Increased activation of CaMKII by both Ca2+ and oxidation is believed to contribute to this process, but evidence is lacking. Marie Haugsten Hansen aimed to provide further insights into the mechanisms behind Ca2+ dependent arrhythmias in CPVT1 and ischemia-reperfusion (IR), and a basis for future improvement in risk stratification, prevention and treatment strategies. The main findings of this work support CaMKII as an interesting target for future treatment strategies in CPVT and IR. Indeed, CaMKII and ROS were demonstrated as important contributors to arrhythmias in these conditions, however, oxidation of M281/282 on CaMKII was not found to be a critical factor in the development of early reperfusion arrhythmias. Testing of antioxidant therapy resulted in protection from Ca2+ dependent arrhythmias in mice. However, antioxidant therapy in a clinically relevant pig model of MI did not protect against myocardial damage or reperfusion arrhythmias. This demonstrates important species differences and the need for testing initial findings for antiarrhythmic therapy in larger animals.
List of papers
Article 1. CaMKII inhibition has dual effects on spontaneous Ca2+ release and Ca2+ alternans in ventricular cardiomyocytes from mice with a gain-of-function RyR2 mutation. Mani Sadredini, Marie Haugsten Hansen, Michael Frisk, William E. Louch, Stephan E. Lehnart, Ivar Sjaastad, Mathis K. Stokke. Am J Physiol Heart Circ Physiol 2021;321(2):H446-H460. doi:10.1152/ajpheart.00011.2021. The article is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1152/ajpheart.00011.2021 |
Article 2. CaMKII and reactive oxygen species contribute to early reperfusion arrhythmias, but oxidation of CaMKIIδ at methionines 281/282 is not a determining factor. Marie Haugsten Hansen, Mani Sadredini, Almira Hasic, Mark E. Anderson, Ivar Sjaastad, Mathis K. Stokke. JMCC 2022; 175: 49-61. DOI: 10.1016/j.yjmcc.2022.12.002. The article is included in the thesis. Also available at:
https://doi.org/10.1016/j.yjmcc.2022.12.002 |
Article 3. Myocardial oxidative stress is increased in early reperfusion, but systemic antioxidative therapy does not prevent ischemia-reperfusion arrhythmias in pigs. Marie Haugsten Hansen, Mani Sadredini, Almira Hasic, Morten Eriksen, Mathis K. Stokke. Front. Cardiovasc. Med., 2023; 10:1223496. DOI: 10.3389/fcvm.2023.1223496. The article is included in the thesis. Also available at: https://doi.org/10.3389/fcvm.2023.1223496 |