The Effect of Remote Ischemic Postconditioning on Quality of Life and Clinical Events after an Ischemic Stroke.

OBJECTIVES: Repeated remote ischemic postconditioning (rIPostC) may be an easily applicable treatment following ischemic stroke to improve quality of life (QoL) and clinical outcomes. rIPostC consists of repeated, brief periods of limb ischemia (through inflation of a blood pressure cuff), followed by reperfusion. This study investigated the 1-year follow-up of rIPostC on QoL and clinical events. METHODS: As part of a randomized controlled trial, adult patients with an ischemic stroke within 24 hours after onset of symptoms were randomized to repeated rIPostC or sham-conditioning. rIPostC was applied twice daily during hospitalization (maximum of 4 days). QoL and patientreported outcome measures (PROMs) were assessed at 12-week and 1-year follow-ups. Additionally, we explored the effect of repeated rIPostC on clinical events (recurrent cerebrovascular events, hospitalization, and mortality). RESULTS: The trial was preliminarily stopped due to limitations in recruitment after the inclusion of 88 patients (rIPostC: 40; sham-conditioning: 48) (70 years, 68% male). Questionnaires were returned by 69 (78%) and 63 (72%) participants after 12 weeks and 1 year, respectively. The median difference of the stroke-specific QoL between rIPostC and sham-conditioning was 0.05 (p =0.986) and -0.16 (p =0.654) after 12 weeks and 1-year, respectively. No significant effect of rIPostC on the different domains of PROMs was detected. We observed no between-group differences in recurrent cerebrovascular events, hospitalization, or all-cause mortality (Hazard Ratios p >0.05). CONCLUSION: In this exploratory analysis, we observed no significant difference between repeated rIPostC and usual care on QoL and clinical outcomes at 12 weeks and 1 year in patients with an ischemic stroke. CLINICAL TRIAL REGISTRATION NUMBER: NTR6880.

The effect of repeated remote ischemic postconditioning after an ischemic stroke (REPOST): A randomized controlled trial.

BACKGROUND AND AIMS: A potential strategy to treat ischemic stroke may be the application of repeated remote ischemic postconditioning (rIPostC). This consists of several cycles of brief periods of limb ischemia followed by reperfusion, which can be applied by inflating a simple blood pressure cuff and subsequently could result in neuroprotection after stroke. METHODS: Adult patients admitted with an ischemic stroke in the past 24 h were randomized 1:1 to repeated rIPostC or sham-conditioning. Repeated rIPostC was performed by inflating a blood pressure cuff around the upper arm (4 × 5 min at 200 mm Hg), which was repeated twice daily during hospitalization with a maximum of 4 days. Primary outcome was infarct size after 4 days or at discharge. Secondary outcomes included the modified Rankin Scale (mRS)-score after 12 weeks and the National Institutes of Health Stroke Scale (NIHSS) at discharge. RESULTS: The trial was preliminarily stopped after we included 88 of the scheduled 180 patients (average age: 70 years, 68% male) into rIPostC (n = 40) and sham-conditioning (n = 48). Median infarct volume was 2.19 mL in rIPostC group and 5.90 mL in sham-conditioning, which was not significantly different between the two groups (median difference: 3.71; 95% CI: -0.56 to 6.09; p = 0.31). We found no significant shift in the mRS score distribution between groups. The adjusted common odds ratio was 2.09 (95% CI: 0.88-5.00). We found no significant difference in the NIHSS score between groups (median difference: 1.00; 95% CI: -0.99 to 1.40; p = 0.51). CONCLUSION: This study found no significant improvement in infarct size or clinical outcome in patients with an acute ischemic stroke who were treated with repeated remote ischemic postconditioning. However, due to a lower-than-expected inclusion rate, no definitive conclusions about the effectiveness of rIPostC can be drawn.

Attenuated inflammatory profile following single and repeated handgrip exercise and remote ischemic preconditioning in patients with cerebral small vessel disease.

Background: Similar to remote ischemic preconditioning bouts of exercise may possess immediate protective effects against ischemia-reperfusion injury. However, underlying mechanisms are largely unknown. This study compared the impact of single and repeated handgrip exercise versus remote ischemic preconditioning on inflammatory biomarkers in patients with cerebral small vessel disease (cSVD). Methods: In this crossover study, 14 patients with cSVD were included. All participants performed 4-day of handgrip exercise (4x5-minutes at 30% of maximal handgrip strength) and remote ischemic preconditioning (rIPC; 4x5-minutes cuff occlusion around the upper arm) twice daily. Patients were randomized to start with either handgrip exercise or rIPC and the two interventions were separated by > 9 days. Venous blood was drawn before and after one intervention, and after 4-day of repeated exposure. We performed a targeted proteomics on inflammation markers in all blood samples. Results: Targeted proteomics revealed significant changes in 9 out of 92 inflammatory proteins, with four proteins demonstrating comparable time-dependent effects between handgrip and rIPC. After adjustment for multiple testing we found significant decreases in FMS-related tyrosine kinase-3 ligand (Flt3L; 16.2% reduction; adjusted p-value: 0.029) and fibroblast growth factor-21 (FGF-21; 32.8% reduction adjusted p-value: 0.029) after single exposure. This effect did not differ between handgrip and rIPC. The decline in Flt3L after repeated handgrip and rIPC remained significant (adjusted p-value = 0.029), with no difference between rIPC and handgrip (adjusted p-value = 0.98). Conclusion: Single handgrip exercise and rIPC immediately attenuated plasma Flt3L and FGF-21, with the reduction of Flt3L remaining present after 4-day of repeated intervention, in people with cSVD. This suggests that single and repeated handgrip exercise and rIPC decrease comparable inflammatory biomarkers, which suggests activation of shared (anti-)inflammatory pathways following both stimuli. Additional studies will be needed to exclude the possibility that this activation is merely a time effect.

Relation between physical activity and cerebral small vessel disease: A nine-year prospective cohort study.

BACKGROUND AND AIMS: Given the unexplored potential of physical activity to reduce the progression of cerebral small vessel disease (cSVD, the purpose of this study was to prospectively (across nine-year follow-up) examine the relation between (baseline) physical activity and the (clinical and imaging) consequences of the whole spectrum of cerebral small vessel disease. METHODS: Five hundred and three patients with cerebral small vessel disease from the RUNDMC study were followed for nine years. Physical activity was assessed using a questionnaire in 2006, 2011, and 2015. Clinical events (i.e. all-cause mortality, cerebrovascular events (by stroke subtype)) were collected with a structured questionnaire. Patients underwent magnetic resonance imaging scanning for the assessment of magnetic resonance imaging markers of cerebral small vessel disease (i.e. white matter hyperintensities, lacunes, and microbleeds) and microstructural integrity of the white matter at three timepoints. RESULTS: The mean age at baseline was 66 (SD 9.0) years; 44% were women. A higher baseline physical activity level was independently associated with a lower all-cause mortality (HR: 0.69, 95%CI: 0.49-0.98, p = 0.03) and incidence of cerebrovascular disease (HR: 0.58, 95%CI: 0.36-0.96, p = 0.03). However, we found no relation between physical activity and incident lacunar stroke or progression of magnetic resonance imaging markers of cerebral small vessel disease. CONCLUSIONS: Whilst regular physical activity was not related to the progression of magnetic resonance imaging markers of cerebral small vessel disease across a nine-year follow-up, results from our study prove that high levels of physical activity in patients with cerebral small vessel disease are associated with a lower all-cause mortality and lower incidence of cerebrovascular events.

The effect of repeated remote ischemic postconditioning on infarct size in patients with an ischemic stroke (REPOST): study protocol for a randomized clinical trial.

BACKGROUND: Remote ischemic postconditioning (rIPostC) refers to the observation that repeated, short periods of ischemia protect remote areas against tissue damage during and after prolonged ischemia. Based on previous observations of a potential neuroprotective effect of rIPostC, the aim of this study is to evaluate whether repeated rIPostC after an ischemic stroke can reduce infarct size, which could be translated to an improvement in clinical outcomes. METHODS/DESIGN: We will enroll 200 ischemic stroke patients to daily rIPostC or sham conditioning during hospitalization into a randomized single-blind placebo-controlled trial. The intervention consists of twice daily exposure to four cycles of 5-min cuff inflation around the upper arm to > 20 mmHg above systolic blood pressure (i.e., rIPostC) or 50 mmHg (i.e., control), followed by 5 minutes of deflation. The primary outcome is infarct size, measured using an MRI diffusion-weighted image at the end of hospitalization. Secondary outcomes include the Modified Rankin Scale, National Institutes of Health Stroke Scale, quality of life, and cardiovascular and cerebrovascular morbidity and mortality. To explore possible underlying mechanisms of rIPostC, venous blood will be sampled to assess biomarkers of inflammation and vascular health. DISCUSSION: Previous studies in animals and humans, using a single bout of remote ischemic conditioning, report a potential effect of rIPostC in attenuating neural damage. Although repeated rIPostC has been investigated for cardiovascular disease patients and preclinical stroke models, no previous study has explored the potential physiological and clinical effects of repeatedly applying rIPostC during the hospitalization phase after a stroke. TRIAL REGISTRATION: Netherlands Trial Register, NTR6880 . Registered on 8 December 2017.

Elevation in blood flow and shear rate prevents hyperglycemia-induced endothelial dysfunction in healthy subjects and those with type 2 diabetes.

Hyperglycemia, commonly present after a meal, causes transient impairment in endothelial function. We examined whether increases in blood flow (BF) protect against the hyperglycemia-mediated decrease in endothelial function in healthy subjects and patients with type 2 diabetes mellitus (T2DM). Ten healthy subjects and 10 age- and sex-matched patients with T2DM underwent simultaneous bilateral assessment of brachial artery endothelial function by means of flow-mediated dilation (FMD) using high-resolution echo-Doppler. FMD was examined before and 60, 120, and 150 min after a 75-g oral glucose challenge. We unilaterally manipulated BF by heating one arm between minute 30 and minute 60. Oral glucose administration caused a statistically significant, transient increase in blood glucose in both groups (P < 0.001). Forearm skin temperature, brachial artery BF, and shear rate significantly increased in the heated arm (P < 0.001), and to a greater extent compared with the nonheated arm in both groups (interaction effect P < 0.001). The glucose load caused a transient decrease in FMD% (P < 0.05), whereas heating significantly prevented the decline (interaction effect P < 0.01). Also, when correcting for changes in diameter and shear rate, we found that the hyperglycemia-induced decrease in FMD can be prevented by local heating (P < 0.05). These effects on FMD were observed in both groups. Our data indicate that nonmetabolically driven elevation in BF and shear rate can similarly prevent the hyperglycemia-induced decline in conduit artery endothelial function in healthy volunteers and in patients with type 2 diabetes. Additional research is warranted to confirm that other interventions that increase BF and shear rate equally protect the endothelium when challenged by hyperglycemia.

Interval exercise, but not endurance exercise, prevents endothelial ischemia-reperfusion injury in healthy subjects.

Endothelial ischemia-reperfusion (I/R) injury importantly contributes to the poor prognosis during ischemic (myocardial) events. Preconditioning, i.e., repeated exposure to short periods of ischemia, effectively reduces endothelial I/R injury. In the present study, we examined the hypothesis that exercise has preconditioning effects on endothelial I/R injury. Therefore, we studied whether an acute bout of endurance or interval exercise is able to protect against endothelial I/R injury. In 17 healthy young subjects, we examined changes in brachial artery endothelial function using flow-mediated dilation (FMD) before and after a bout of high-intensity interval exercise, moderate-intensity endurance exercise, or a control intervention. Subsequently, I/R injury was induced by inflation of a blood pressure cuff around the upper arm to 220 mmHg for 20 min and 20 min of reperfusion followed by another FMD measurement. Near-infrared spectrometry was used to examine local tissue oxygenation during exercise. No differences in brachial artery FMD were found at baseline for the three conditions. I/R induced a significant decline in FMD (7.1±2.3 to 4.3±2.3, P<0.001). When preceded by the interval exercise bout, no change in FMD was present after I/R (7.7±3.1 to 7.2±3.1, P=0.56), whereas the decrease in FMD after I/R could not be prevented by the endurance exercise bout (7.8±3.1 to 3.8±1.7, P<0.001). In conclusion, a single bout of lower limb interval exercise, but not moderate-intensity endurance exercise, effectively prevents brachial artery endothelial I/R injury. This indicates the presence of a remote preconditioning effect of exercise, which is selectively present after short-term interval but not continuous exercise in healthy young subjects.