Stroke, sometimes referred to as a “brain attack”, is a medical emergency and a leading cause of death around the world, occurring when the blood supply to a part of the brain is interrupted or reduced, depriving brain tissue of oxygen and nutrients. Such deficit can happen when a blood vessel in the brain bursts (Hemorrhagic stroke) or, more commonly, when a blockage develops (Ischemic stroke). If not treated immediately, brain cells begin to die within minutes, resulting in serious disability or death.
Sleep-disordered breathing (SDB), and especially its most common form - obstructive sleep apnea (OSA), has been associated with increased risk for ischemic stroke. Recently, a large prospective cohort study followed 5422 individuals without a history of stroke for a median of 8.7 years1. Chances of ischemic stroke in men were shown to be increased with OSA severity (as measured by AHI), even after adjustment for potential confounders (adjusted hazard ratio [HR] 2.86, 95% CI 1.10-7.39). Overall OSA was found to be associated with an approximately three-fold increase risk of ischemic stroke in men, resonating findings from previous studies that demonstrated 4- to 6-fold higher prevalence of OSA in stroke patients2. Moreover, it had been shown that treatment of OSA decrease mortality and improve functional recovery after stroke3.
This strong connection between OSA and stroke is not surprising considering the fact that OSA affects all major risk factors of stroke: hypertension, hyperlipidemia, hypoxemia, diabetes and atrial fibrillation. However, the underlying mechanisms by which OSA increases the risk, independent of these traditional risk factors, have not been established. Nevertheless, some notable attempts to suggest a causal mechanism have been made. Here are examples of two such suggested mechanisms:
Decreased cerebral blood flow velocity: Ordinarily, the brain regulates its blood flow to meet its own metabolic needs, even in the face of changes in blood pressure, a process known as cerebral autoregulation. The repeated surges and drops in blood pressure, oxygen level and blood flow during numerous apnea episodes each night, reduces the brain’s ability to regulate these functions. This mechanism was demonstrated by a study conducted at Yale Center for Sleep Medicine4; 48 subjects, 22 diagnosed with OSA (AHI≥30) and 26 controls (AHI<5), free of cerebrovascular and active coronary artery disease, participated in this study. Cerebral autoregulation was examined by measuring cerebral artery blood flow velocity (CBFV) and arterial blood pressure during orthostatic hypotension and recovery as well as during 5% CO2 inhalation. The findings showed that patients with OSA have decreased CBFV at baseline compared to controls (8±3 vs. 55±2 cm/s; P<0.05, respectively) and delayed cerebrovascular compensatory response to changes in blood pressure (CBFV: 0.06±0.02 vs. 0.20±0.06 cm∙s-2∙mmHg-1; P<0.05, figure 1). These perturbations may increase the risk of cerebral ischemia during obstructive apnea.
Figure 1: Rate of change of vascular conductance in response to orthostatic hypotension as a measure of cerebral autoregulation. The OSA patients (B) had significantly lower compensatory rate (the slope of CBFV/MAP/time) (P<0.05) and longer time course than the control (A).
Hypercoagulability and inflammation: Another suggested mechanism relates to the hypercoagulability and increased platelet aggregation related to OSA, which in turn increase risk of blood vessels' blockage. This mechanism was recently demonstrated by a group of researchers from the Israeli Soroka Clinical Research Center5. 43 patients underwent a nocturnal respiratory assessment during the first 48 hours after stroke symptoms onset. In addition, Serum samples were obtained from all the study participants at the first morning after their admission, in order to track the concentration of some proinflamatory and procoagulant factors. Almost 90% of the patients had SDB (AHI>5) with 51% diagnosed with OSA (AHI ≥15), strengthening previous findings of high prevalence of SDB in patients with stroke. As the mechanism predicted, AHI was found to be correlated with indicators of inflammation and coagulability: IL-6 (ρ=0.37, P=0.02) and PAI-1 (ρ=0.31, P=0.07). PAI-1 was negatively correlated with a saturation nadir (ρ=−0.47, P=0.005) and positively correlated with a desaturation index (ρ=0.41, P=0.02). PAI-1 (pg/mL) was significantly higher in patients with an AHI≥15; mean of 176.64±74.52 versus 98.48±52.58 pg/mL, P=0.003 (Figure 2A). IL-6 (pg/mL, 6.64±5.27 versus 3.14±2.05, P=0.006, Figure 2B) and TNF (pg/mL, 6.39±5.00 versus 3.57±1.87, P=0.022, Figure 2C) were similar.
Figure 2: A, Plasminogen activator inhibitor-1 (PAI-1) levels stratified by apnoea hyponoea index (AHI). PAI-1 concentration (pg/mL) was significantly higher in serum drawn from patients with AHI≥15 than in patients with AHI<15. B, Interleukin-6 (IL-6) levels stratified by AHI. IL-6 concentration (pg/mL) was significantly higher in serum drawn from patients with AHI≥15. C, Tumor necrosis factor (TNF)-α levels stratified by AHI. TNF concentration (pg/mL) was significantly higher in serum drawn from patients with AHI≥15. Horizontal lines represent median values; the upper and lower box limits indicate the 25th and 75th percentile; whiskers represent the 10th and 90th percentiles.
The clinical importance of the last described study goes beyond the mechanism demonstration - it was the first time the respiratory assessment in stroke patients was evaluated using WatchPAT. Since WatchPAT technology is easily used as a bed-side measure in the acute post stroke period and enables rapid diagnosis and therapeutic recommendations, it’s ideal for improvement of secondary prevention.
WatchPAT, Home Sleep Apnea Test device, is an easy to use, effective and accurate tool for OSA diagnosis. You may learn more about WatchPAT and our comprehensive “Total Sleep Solution” for Cardiology practices in www.cardiosleepsolutions.com
- Redline, S., Yenokyan, G., Gottlieb, D. J., Shahar, E., O'Connor, G. T., Resnick, H. E., ... & Ali, T. (2010). Obstructive sleep apnea–hypopnea and incident stroke: the sleep heart health study. American journal of respiratory and critical care medicine, 182(2), 269-277.
- Bassetti, C. L., Milanova, M., & Gugger, M. (2006). Sleep-disordered breathing and acute ischemic stroke: diagnosis, risk factors, treatment, evolution, and long-term clinical outcome. Stroke, 37(4), 967-972.
- Ryan, C. M., Bayley, M., Green, R., Murray, B. J., & Bradley, T. D. (2011). Influence of continuous positive airway pressure on outcomes of rehabilitation in stroke patients with obstructive sleep apnea. Stroke, STROKEAHA-110.
- Urbano, F., Roux, F., Schindler, J., & Mohsenin, V. (2008). Impaired cerebral autoregulation in obstructive sleep apnea. Journal of applied physiology, 105(6), 1852-1857.
- Ifergane, G., Ovanyan, A., Toledano, R., Goldbart, A., Abu-Salame, I., Tal, A., ... & Novack, V. (2016). Obstructive sleep apnea in acute stroke: a role for systemic inflammation. Stroke, 47(5), 1207-1212.