Disruptions of Circadian Rhythms and Thrombolytic Therapy During Ischemic Stroke Intervention

Abstract

Several endogenous and exogenous factors interact to influence stroke occurrence, in turn contributing to discernable daily distribution patterns in the frequency and severity of cerebrovascular events. Specifically, strokes that occur during the morning tend to be more severe and are associated with elevated diastolic blood pressure, increased hospital stay, and worse outcomes, including mortality, compared to strokes that occur later in the day. Furthermore, disrupted circadian rhythms are linked to higher risk for stroke and play a role in stroke outcome. In this review, we discuss the interrelation among core clock genes and several factors contributing to ischemic outcomes, sources of disrupted circadian rhythms, the implications of disrupted circadian rhythms in foundational stroke scientific literature, followed by a review of clinical implications. In addition to highlighting the distinct daily pattern of onset, several aspects of physiology including immune response, endothelial/vascular and blood brain barrier function, and fibrinolysis are under circadian clock regulation; disrupted core clock gene expression patterns can adversely affect these physiological processes, leading to a prothrombotic state. Lastly, we discuss how the timing of ischemic onset increases morning resistance to thrombolytic therapy and the risk of hemorrhagic transformation.

The role of circadian clock in astrocytes: From cellular functions to ischemic stroke therapeutic targets

“…As research progresses and substantial evidence indicates that circadian rhythms govern astrocyte function and injury response, treatment should consider that its molecular targets may be oscillatory and may require different doses at different times of the day. Evidence supports the role of time-of-day changes in the efficacy of rt-PA and hemorrhagic transformation as a potential negative consequence of rt-PA administration (Marler et al, 1989;Liu et al, 2021). Several clinical trials have been attempted and have shown that intravenous thrombolysis with rt-PA between 6:00 a.m. and 6:00 p.m. appears to be less effective and safer, and in patients who start intravenous thrombolysis between noon and midnight, the hemorrhagic transformation rate is lower (Cappellari et al, 2014;Liu et al, 2021).…”

“…Evidence supports the role of time-of-day changes in the efficacy of rt-PA and hemorrhagic transformation as a potential negative consequence of rt-PA administration (Marler et al, 1989;Liu et al, 2021). Several clinical trials have been attempted and have shown that intravenous thrombolysis with rt-PA between 6:00 a.m. and 6:00 p.m. appears to be less effective and safer, and in patients who start intravenous thrombolysis between noon and midnight, the hemorrhagic transformation rate is lower (Cappellari et al, 2014;Liu et al, 2021). Another study found that thrombolysis performed during the day (9:00 a.m. to 9:00 p.m.) had better outcomes compared to nighttime (9:00 p.m. to 9:00 a.m.) (Vilas et al, 2012).…”

Circadian Factors in Stroke: A Clinician’s Perspective

“…Other treatments (antiplatelet [ 151 ], anticoagulants [ 152 ], thrombolytic drugs [ 153 , 154 ], etc.) might have a greater capacity within the chronotherapy approach, although further investigation is needed [ 47 ].…”

“…However, the NINDS rt-PA Stroke Trial ( n = 624) did not find any association between the stroke onset time (and rt-PA treatment given within 3 h of stroke onset) and 3-month outcomes, although there was an association with the occurrence of a symptomatic intracranial hemorrhage within 36 h: patients with stroke onset between 04:01 and 08:00 who received rt-PA had a lower risk of having a symptomatic intracranial hemorrhage [ 13 ]. Some authors explain such an effect by the endogenous circadian rhythm in blood–brain barrier permeability, which shows reduced trafficking during the active phase compared to other periods during the day [ 154 ].…”

Influence of Temperature Chronobiology on Stroke Outcome

“…This well-established temporal risk was observed for ischemic and haemorrhage strokes [ 22 , 23 ], although some slight differences were observed in stroke TOAST (Trial of Org 10,172 in Acute Stroke Treatment) subtypes [ 24 ]. The consideration of circadian rhythms may be necessary in order to optimise therapeutic approaches due to the variability of patient response to ischemic stroke and its therapies as well as factors explaining the lack of consistency with the patients’ evolution [ 25 ]. Interestingly, physiological body temperature starts to increase in the morning [ 11 ], coinciding with the period when the peak of stroke has been described [ 22 , 23 , 24 ], and decreases during the sleep period, when the incidence of stroke is lower [ 26 ].…”