International Stroke Conference
January 24–26

A conversation with David Hess, MD, vascular neurologist and Dean of the Medical College of Georgia, on Remote Ischemic Conditioning at the Internal Stroke Conference 2018.

Interviewed by Alexis N. Simpkins, MD, PhD, University of Florida.

Remote ischemic conditioning (RIC) was the focus of several talks and posters at the 2018 International Stroke Conference, focusing on the utility of RIC in a range of cerebrovascular disease from acute ischemic stroke, to small vessel disease, to subarachnoid hemorrhage. Remote ischemic conditioning involves temporarily decreasing blood flow typically to a limb such as the arm and then reperfusing the limb serially with the goal of creating a milieu in the blood that will mimic an ischemia tolerate state. The data presented summarized the most common adverse events and intolerances (skin petechia and pain in the extremity), feasibility in the clinical setting, and probably mechanism of action of RIC. Dr. David Hess participated in a question-and-answer interview following the conference about the future of RIC in the field of stroke.

Dr. Simpkins: In theory, patients presenting with cerebrovascular disease are likely to have some degree of endothelial dysfunction. How much does RIC depend on the baseline functional endothelial function of the patients?

Dr. Hess: We do not fully understand the mechanism of action of RIC. There are two broad theories: the “humoral,” where a blood-borne substance mediates the effects, and the “neurogenic,” where the effect is mediated by the nervous system. There has been concern in the cardiac field that older patients and diabetics may not benefit as much as younger patients. However, our data shows that older mice benefit from RIC in stroke and VCID models, and a study by Xunming Ji’s group in Beijing showed that even human subjects with intracranial atherosclerosis older than 80 benefit.

Our thinking is that nitric oxide is important for the effects on the brain. We consistently see increases of cerebral blood flow with RIC, and this is only in areas of ischemia. While nitric oxide generated by shear stress in the limb from RIC would have a short life, NO has an “endocrine” effect likely mediated by nitrite or is transmitted by the red blood cell. While the conventional thinking was that eNOS was restricted to endothelium, we now know it is also in the red blood cell and other circulating blood cells. This blood cell eNOS may “bail out” an impaired cerebrovascular endothelium.

Dr. Simpkins: RIC had been investigated in several types of cardiovascular disorders. How would you envision RIC being used in clinical practice?

Dr. Hess: I see RIC being utilized in three types of cerebrovascular disorders and in three time periods.

Acute RIC (preconditioning) is ideal for acute ischemic stroke and possibly intracerebral hemorrhage where ultra-early treatment would be important. RIC might benefit stroke patients even more if it was extended in the post-reperfusion period (post conditioning). Goethe Andersen (Aarhus, Denmark) has been the leader in this area and has conducted an early phase II trial and is about to begin a 2500-subject randomized clinical trial in the ambulance in Denmark (RESIST).

The other use is a “subacute use” such as in subarachnoid hemorrhage to reduce the risk of delayed cerebral ischemia. Sebastian Koch (Miami) and Nestor Gonzalez are pioneers in this area and have conducted early phase trials and are planning more.

The third area is chronic RIC or (C-RIC) that has been used successfully by Xunming Ji’s group in patients with intracranial atherosclerosis and cerebral small vessel disease. They have used it for periods as long as a year with good tolerability. I feel small vessel and white matter disease is a huge growth area as we have no targeted treatments. We know from observational studies that physical exercise may help; RIC is an exercise mimetic and shares common mechanisms with exercise, so there is a strong rationale to test in patients with small vessel and white matter disease.

Dr. Simpkins: What do you feel are the next critical research questions to address regarding use of RIC and cerebrovascular disease?

Dr. Hess: For me, the critical questions are the optimal dose and duration. For example, in C-RIC, do we need to use cuffs on both arms twice per day, or could we use lower doses, such as one arm every other day? Do we need to treat for 6 months, 1 year, or forever?  If we use this treatment chronically, we have to make sure the patients are able to adhere to treatment.

We also need better understanding of the mechanism of action and biomarkers. Blood biomarkers to measure the conditioning effect are needed. We are interested in measuring RBC eNOS in the blood as this is possible by flow cytometry. Similarly, imaging biomarkers to look at cerebral blood flow, such as MRI ASL, need standardization to be developed for use in clinical trials.