Christine Ramjee

Introduction: Sudden Cardiac Death (SCD) is death that occurs within one hour of the loss of heart function or adequate perfusion to the body. The etiology of SCD is due to either acquired or genetic cardiovascular disease, but most commonly, any patient with prior cardiac dysrhythmias is at a much higher risk.^1,2,3 With a ~20% mortality rate,² SCD has a broad impact with limited prevention strategies. While there are many genetic and cellular mechanisms associated with SCD, current research is delving into the circadian clock, the biological timekeeping mechanism that regulates bodily functions, including the cardiovascular system.^4,5 Since there is a peak of SCD onset in the morning hours, controlling core circadian clock genes could better illuminate the underpinnings of SCD onset, and provide targets for future prophylactic treatments.^5,6 Methods and Results: To confirm pathologic expression of circadian clock genes, left ventricular tissue samples obtained from three groups: 1) patients with end-stage heart failure and a history of ventricular dysrhythmias; 2) patients with end-stage heart failure without a history of arrhythmic burden and; 3) non-failing hearts were analyzed for rhythmic gene expression using PCR anaylsis.⁷ The data identified significant expression patterns in failing human hearts for five circadian genes: ARNTL, DBP, NFIL3, NR1D1, and PER2.⁷ We chose to focus on two regulatory paths: NR1D1 and ARNTL/PER2 (both controlled by the Clock gene). NR1D1/2 codes for the REV-ERB⍺/ꞵ nuclear receptors which lack an active domain, and thus are integral to the negative feedback control of the core circadian clock mechanism.^8,9 Meanwhile, ARNTL and Clock (which produces the transcription factor Circadian Locomotor Output Cycles Kaput, or CLOCK) form the positive feedback control of the circadian clock gene loop.^10,11 Through gene expression analysis, quantifying changes in cardiac function through electrocardiograms (ECGs), mitochondrial and autophagy function, the impacts of differential NR1D1/2 and Clock expression on two models of rodent heart failure (simulated myocardial infarction and ischemia-reperfusion) illustrated that both genes had pathologic ramifications in recovery before and after cardiac injury. Further, treating cardiac injury models using REV-ERB agonist SR9009 significantly reduced the impact and lethality of myocardial infarctions,⁹ while the antiarrhythmic Moricizine was shown to decrease Clock expression.¹¹ Conclusion: New therapeutics that target the REV-ERBs (like SR9009), Clock and other core circadian clock factors, to improve cardiac function after cardiovascular injury and mitigate risk factors for SCD, are a prime source for research and development for future clinical trials.

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