Central and peripheral clocks synergistically enhance circadian robustness, flexibility and performance of cardiac pacemaking

The strong circadian ([~]24h) rhythms in heart rate (HR) are critical for flexible regulation of cardiac pacemaking function throughout the day. While this circadian flexibility in HR is robustly sustained in diverse conditions, it declines as the heart ages, accompanied by reduced maximal HR performance. The intricate regulation of circadian HR patterns involves the orchestration of sympathetic and parasympathetic nervous activities (SNA and PNA) alongside local circadian rhythmicity (LCR) within the heart. However, their intricate interactions that sustain the resilience and adaptability of circadian rhythms, as well as the mechanisms that underpin their deterioration during the aging process, remain enigmatic. To address these questions, we developed a mathematical model describing autonomic control and LCR in sinoatrial nodal cells (SANC) that accurately captures distinct circadian patterns in adult and aged mice. Our model underscores the indispensable synergy among SNA, PNA, and LCR in preserving circadian flexibility, robustness, and performance in SANC. SNA predominantly enhances SANC robustness and performance, while PNA primarily drives SANC flexibility, complemented by LCR and SNA. LCR acts as a booster, further enhancing SANC flexibility and performance. However, the delicate balance of this synergy is disrupted with age, resulting in diminished SANC performance and flexibility. Specifically, age-related impairment of PNA selectively dampens SANC flexibility while ion channel remodeling disrupts all SANC functions. Our work shed light on their critical synergistic interactions in regulating time-of-day cardiac pacemaking function and dysfunction, which may help to identify potential therapeutic targets within the circadian clock for the prevention and treatment of cardiac arrhythmias. Author SummaryThe mammalian heart relies on the sinoatrial node, known as the cardiac pacemaker, to orchestrate heartbeats. These heartbeats slow down during sleep and accelerate upon waking, in anticipation of daily environmental changes. The hearts ability to rhythmically adapt to these 24-hour changes, known as circadian rhythms, is crucial for flexible cardiac performance throughout the day, accommodating various physiological states. However, with aging, the hearts circadian flexibility gradually weakens, accompanied by a decline in maximal heart rate. Previous studies have implicated the involvement of a master circadian clock and a local circadian clock within the heart, but their time-of-day interactions and altered dynamics during aging remain unclear. In this study, we developed a mathematical model to simulate the regulation of sinoatrial nodal cell pacemaking function by the master and local circadian clocks in adult and aged mice. Our results revealed distinct roles played by these clocks in determining circadian patterns of sinoatrial nodal cells and shed light on their critical synergistic interactions in regulating time-of-day cardiac pacemaking function and dysfunction.