Multifaceted mechanism for ischemic preconditioning could help explain stroke resilience
Remote ischemic preconditioning could improve brain function by inducing a number of key adaptive responses in dynamic cerebral autoregulation and biomarker levels, according to a study of healthy adults.
Fifty people underwent preconditioning as a 40-minute procedure in which brief cycles of ischemia and reperfusion were applied to the arms and legs by blood pressure cuffs of an automatic machine.
Continuous cerebral blood flow velocity and continuous arterial blood pressure measurements 6 hours later suggested improved regulation of cerebral hemodynamics, and this was sustained for 24 hours, according to Yi Yang, MD, PhD, of The First Hospital of Jilin University in Changchun, China, and colleagues reporting in the July 2 issue of Neurology.
Moreover, study participants showed elevations in two neuroprotective factors and four inflammation-related biomarkers just 1 hour after remote ischemic preconditioning, the investigators said:
- Glial cell-derived neurotrophic factor: a potential novel candidate of defense against ischemic brain injury
- Vascular endothelial growth factor-A: inducer of vasodilation, angiogenesis, neuroprotection, and neurogenesis
- Transforming growth factor-β1: promotes neurovascular repair and regulates immune system function
- Leukemia inhibitory factor: plays a role in endogenous neuroprotective mechanisms
- Matrix metallopeptidase-9: related to brain edema after acute cerebral infarction
- Tissue inhibitor of metalloproteinase-1: protects the blood-brain barrier and is related to tissue remodeling and inflammation in ischemic stroke
Inflammation marker monocyte chemoattractant protein-1, involved in the advanced stage of atherosclerotic cerebrovascular disease, went down.
"This eloquent study shows how RIPC [remote ischemic preconditioning] induces a number of key adaptive responses at the level of a complex brain vascular adaptation, via adaptive changes in cerebral autoregulation, and changes at the tissue level where RIPC may prime at-risk brain parenchyma and vasculature for future ischemia," according to an accompanying editorial.
"It gives us a unique insight into how some of our patients with multiple stroke risk factors seem to avoid devastation with the inevitable onset of ischemic stroke," wrote editorialists Paul Nyquist, MD, MPH, of the Johns Hopkins School of Medicine in Baltimore, Maryland, and Marios Georgakis, MD, MSc, of Germany's University Hospital of Ludwig-Maximilians-Universität in Munich.
Preconditioning on remote tissues and organs is thought to render the heart and the brain resistant to a subsequent prolonged ischemia insult.
"Studies of cardiovascular diseases have repeatedly shown that RIPC could significantly reduce infarct size after myocardial ischemia in both animals and human patients," according to Yang's group. "It has been shown that RIPC activates both neuronal signals and humoral factors to confer its protective effects on remote tissues and organs, but the underlying mechanisms, especially in the brain, remain unclear."
The 50-person study cohort was age 34 on average, and 22 were men. All were Asian.
These individuals underwent serial assessments for blood brain flow before and after preconditioning. However, there was only one blood sample taken post-procedure, which was a limitation of the study.
Another weakness was that this was a small group of healthy adults.
"Hypertension, older age, atherosclerosis, and cerebral small vessel disease all impair cerebral autoregulation. Thus, individuals with cerebrovascular disease who might actually benefit may not have the observed dCA [dynamic cerebral autoregulation] response to RIPC," commented Nyquist and Georgakis.
"Furthermore, the blood-based biomarkers might reflect locally induced changes, not changes occurring in the brain," the duo suggested.
Nevertheless, the study marks an "important and ingenious step" toward bringing the research on preconditioning to clinical practice and finding the mechanisms for the preservation of tissue when there is ischemic injury to the brain, they said.
"Only a well-designed clinical trial testing the efficacy of RIPC can answer questions about the ability of RIPC to prevent clinical endpoints and to limit volume loss after an ischemic insult. Despite the difficulties with the early identification of at-risk groups, such a trial would be novel and would involve an easily applied intervention with minimal risk and low intrinsic costs," according to Nyquist and Georgakis.
The study was funded by grants from the National Key R&D Program of China and the Program for the JLU Science and Technology Innovative Research Team.
Yang disclosed no relevant conflicts.
Nyquist reported receiving funding from the NIH and the U.S. Navy.
Georgakis declared funding from the German Academic Exchange Service and the Onassis Foundation.
Source Reference: Guo Z, et al "Changes in cerebral autoregulation and blood biomarkers after remote ischemic preconditioning" Neurology 2019; DOI: 10.1212/WNL.0000000000007732.
Source Reference: Nyquist P, Georgakis MK "Remote ischemic preconditioning effects on brain vasculature" Neurology 2019; DOI: 10.1212/WNL.0000000000007724.
Read the original article on Medpage Today: Brain Feels the Squeeze of BP Cuffs in Multiple Possibly Helpful Ways