Daniaal Saeed

Introduction: Myocardial infarction (MI) results from prolonged ischemia to the myocardium of the heart caused by stenosis of the coronary arteries that perfuse the heart.^1,2 Despite the fact that MI is an acute event, many long-term lifestyle factors such as environment, diet, genetics, exercise habits, and even gender can increase the likelihood of patients experiencing MI, making it one of the most globally diagnosed illnesses.¹  Peripheral circadian clocks present in all types of cells in the heart are able to regulate various cardiac functions including: endothelial function, blood pressure, heart rate, and potentially cardiac healing.¹ Emerging areas of research focusing on the relationship between cardiovascular disease and the potential roles of circadian rhythm in healing are working to identify circadian genes that help play roles in healing cardiovascular tissue post-MI, as well as playing a cardio-protective role to prevent pathologies from occurring. Methods: To determine whether circadian genes play a role in cardiac healing post-MI, genetically modified knockout CLOCK Δ19/Δ19 mice were compared against wild type (WT) mice.^3,4,5,6 All mice were housed in complete dark environments to avoid any confounding variables, and within one to four hours after turning lights on, researchers subjected knockout and control group mice to surgical ligation of the left anterior descending (LAD) artery in order to mimic MI. After forty-five minutes, researchers reopened the wound and removed the sutures from the LAD arteries of the mice to allow cardiac reperfusion.^3,4,5,6 Results: Stained tissue from the ventricular myocardium of WT and knockout mice showed that mice in the CLOCK Δ19/Δ19 knockout group had a higher number of dead ventricular myocytes after allowing reperfusion to occur.^3,4 The data also suggests that CLOCK Δ19/Δ19 show signs of mitochondrial dysfunction such as increased production of reactive oxygen species and loss of mitochondrial membrane potential, which can lead to even higher likelihood of cardiac damage during ischemic stress.³ Conclusion: The data shows that mice with intact clock genes demonstrated better outcomes and decreased mitochondrial dysfunction when compared to the CLOCK Δ19/Δ19 knockout mice.^{3,4, 6} There is still much to learn surrounding the role of circadian genes in cardiac healing and protection, and continuing research should aim to identify the specific pathways and proteins involved in healing post-MI.

1. Pagliaro BR, Cannata F, Stefanini GG, Bolognese L. Myocardial ischemia and coronary disease in heart failure. Heart Fail Rev. 2020;25(1):53-65.
2. Crnko S, Du Pre BC, Sluijter JPG, Van Laake LW. Circadian rhythms and the molecular clock in cardiovascular biology and disease. Nat Rev Cardiol. 2019;16(7):437-447.
3. Rabinovich-Nikitin I, Rasouli M, Reitz CJ, et al. Mitochondrial autophagy and cell survival is regulated by the circadian Clock gene in cardiac myocytes during ischemic stress. Autophagy. 2021;17(11):3794-3812.
4. Mistry P, Reitz CJ, Khatua TN, et al. Circadian influence on the microbiome improves heart failure outcomes. J Mol Cell Cardiol. 2020;149:54-72.
5. Podobed P, Pyle WG, Ackloo S, et al. The day/night proteome in the murine heart. Am J Physiol Regul Integr Comp Physiol. 2014;307(2):R121-R137. doi:10.1152/ajpregu.00011.2014
6. Alibhai FJ, Reitz CJ, Peppler WT, et al. Female ClockΔ19/Δ19 mice are protected from the development of age-dependent cardiomyopathy. Cardiovasc Res. 2018;114(2):259-271. doi:10.1093/cvr/cvx185