A Prospective Transcranial Doppler Ultrasound-Based Evaluation of the Effects of Repetitive Subconcussive Head Trauma on Neurovascular Coupling Dynamics.

OBJECTIVE: To determine the effects of repetitive subconcussive head trauma on neurovascular coupling (NVC) responses. DESIGN: Prospective cohort study collected between September 2013 and December 2016. SETTING: University laboratory. PARTICIPANTS: One hundred seventy-nine elite, junior-level (age, 19.6 ± 1.5 years) contact sport (ice hockey, American football) athletes recruited for preseason testing. Fifty-two nonconcussed athletes returned for postseason testing. Fifteen noncontact sport athletes (age, 20.4 ± 2.2 years) also completed preseason and postseason testing. EXPOSURE(S): Subconcussive sport-related head trauma. MAIN OUTCOME MEASURES: Dynamics of NVC were estimated during cycles of 20 seconds eyes closed and 40 seconds eyes open to a visual stimulus (reading) by measuring cerebral blood flow (CBF) velocity in the posterior (PCA) and middle (MCA) cerebral arteries via transcranial Doppler ultrasound. RESULTS: Both athlete groups demonstrated no significant differences in PCA or MCA NVC dynamics between preseason and postseason, despite exposure to a median of 353.5 (range, 295.0-587.3) head impacts (>2g) over the course of the season for contact sport athletes. CONCLUSIONS: Within the context of growing concern over detrimental effects of repetitive subconcussive trauma, the current results encouragingly suggest that the dynamics of NVC responses are not affected by 1 season of participation in junior-level ice hockey or American football. This is an important finding because it indicates an appropriate postseason CBF response to elevated metabolic demand with increases in neural activity.

Factor XI inhibition in cardiovascular disease.

Cardiovascular disease remains the leading global cause of mortality, requiring effective antithrombotic strategies to prevent thromboembolic events. Currently available therapies are effective but have inherent bleeding risks which may limit or preclude their use, particularly in patients at the highest risk of bleeding. Factor XI (FXI) inhibitors are a promising new class of anticoagulants which may mitigate the risk of bleeding while maintaining efficacy. Further, they have the potential to provide effective anticoagulation in indications where direct oral anticoagulants (DOACs) are proven less effective than vitamin K antagonists (VKAs) or when DOACs are contraindicated. The development of FXI inhibitors was based on mechanistic considerations suggesting FXI's role in thrombus formation without significantly affecting hemostasis, supported by epidemiological data and animal experiments. FXI inhibitors, including antisense oligonucleotides, monoclonal antibodies, and small­molecule inhibitors, target different stages of FXI production or activation, offering a diversity of therapeutic options with differing onset and offset of action, drug interaction potential, and renal elimination. FXI inhibitors have shown potential benefits in phase II trials, demonstrating similar or reduced bleeding rates to existing agents, including DOACs. The early termination of AZALEA­TIMI 71 (Safety and Tolerability of Abelacimab [MAA868] vs Rivaroxaban in Patients With Atrial Fibrillation) and OCEANIC­AF (A Study to Learn How Well the Study Treatment Asundexian Works and How Safe it is Compared to Apixaban to Prevent Stroke or Systemic Embolism in People With Irregular and Often Rapid Heartbeat [Atrial Fibrillation], and at Risk for Stroke) trials underscores challenges in the selection of appropriate patient populations and anticoagulant class, agent, and dose. Ongoing phase III trials including OCEANIC­STROKE (A Study to Test Asundexian for  Preventing a Stroke Caused by a Clot in Participants After an Acute Ischemic Stroke or After a High­risk Transient Ischemic Attack, a So­called Mini Stroke) and LIBREXIA trials aim to further explore the efficacy of FXI inhibitors in stroke, acute coronary syndrome, and atrial fibrillation. In conclusion, FXI inhibitors hold promise as next­generation anticoagulants, potentially addressing limitations of current therapies. Ongoing research is required to establish their place in clinical practice and address unresolved questions.

Cerebral Autoregulation Is Disrupted Following a Season of Contact Sports Participation.

Repetitive subconcussive head impacts across a season of contact sports participation are associated with a number of deficits in brain function. To date, no research has investigated the effect of such head impact exposure on dynamic cerebral autoregulation (dCA). To address this issue, 179 elite, junior-level (age 19.6 ± 1.5 years) contact sport (ice hockey, American football) athletes were recruited for pre-season testing. Fifty-two non-concussed athletes returned for post-season testing. Fifteen non-contact sport athletes (age 20.4 ± 2.2) also completed pre- and postseason testing. dCA was assessed via recordings of beat-by-beat mean arterial pressure (MAP) and middle cerebral artery blood velocity (MCAv) using finger photoplethysmography and transcranial Doppler ultrasound, respectively, during repetitive squat-stand maneuvers at 0.05 and 0.10 Hz. Transfer function analysis was used to determine Coherence (correlation), Gain (response amplitude), and Phase (response latency) of the MAP-MCAv relationship. Results showed that in contact sport athletes, Phase was reduced (p = 0.027) and Gain increased (p < 0.001) at post-season compared to pre-season during the 0.10 Hz squat-stand maneuvers, indicating cerebral autoregulatory impairment in both the latency and magnitude of the response. Changes in Phase were greater in athletes experiencing higher numbers and severity of head impacts. By contrast, no changes in dCA were observed in non-contact sport controls. Taken together, these results demonstrate that repetitive subconcussive head impacts occurring across a season of contact sports participation are associated with exposure-dependent impairments in the cerebrovascular pressure-buffering system capacity. It is unknown how long these deficits persist or if they accumulate year-over-year.

Sport-Related Concussion Alters Indices of Dynamic Cerebral Autoregulation.

Sport-related concussion is known to affect a variety of brain functions. However, the impact of this brain injury on cerebral autoregulation (CA) is poorly understood. Thus, the goal of the current study was to determine the acute and cumulative effects of sport-related concussion on indices of dynamic CA. Toward this end, 179 elite, junior-level (age 19.6 ± 1.5 years) contact sport (ice hockey, American football) athletes were recruited for preseason testing, 42 with zero prior concussions and 31 with three or more previous concussions. Eighteen athletes sustained a concussion during that competitive season and completed follow-up testing at 72 h, 2 weeks, and 1 month post injury. Beat-by-beat arterial blood pressure (BP) and middle cerebral artery blood velocity (MCAv) were recorded using finger photoplethysmography and transcranial Doppler ultrasound, respectively. Five minutes of repetitive squat-stand maneuvers induced BP oscillations at 0.05 and 0.10 Hz (20- and 10-s cycles, respectively). The BP-MCAv relationship was quantified using transfer function analysis to estimate Coherence (correlation), Gain (amplitude ratio), and Phase (timing offset). At a group level, repeated-measures ANOVA indicated that 0.10 Hz Phase was significantly reduced following an acute concussion, compared to preseason, by 23% (-0.136 ± 0.033 rads) at 72 h and by 18% (-0.105 ± 0.029 rads) at 2 weeks post injury, indicating impaired autoregulatory functioning; recovery to preseason values occurred by 1 month. Athletes were cleared to return to competition after a median of 14 days (range 7-35), implying that physiologic dysfunction persisted beyond clinical recovery in many cases. When comparing dynamic pressure buffering between athletes with zero prior concussions and those with three or more, no differences were observed. Sustaining an acute sport-related concussion induces transient impairments in the capabilities of the cerebrovascular pressure-buffering system that may persist beyond 2 weeks and may be due to a period of autonomic dysregulation. Athletes with a history of three or more concussions did not exhibit impairments relative to those with zero prior concussions, suggesting recovery of function over time. Findings from this study support the potential need to consider physiological recovery in deciding when patients should return to play following a concussion.