COVID-19: Oxidative Preconditioning as a Potential Therapeutic Approach.

This Article summarizes the likely benefits of central nervous system oxidative preconditioning in the reduction of COVID-19 based on its putative pathogenesis. The current COVID-19 outbreak caused a pandemic with millions of infected patients and death cases worldwide. The clinical features of severe acute respiratory syndrome coronavirus (SARS-CoV) was initially linked with respiratory disorders, but recent studies have reported alterations of neurological and cerebrovascular functions in COVID-19 patients. The main viral infection features are related to cell death, inflammation, and cytokine generation, which can be associated with the dysregulation of redox systems or oxidative stress. However, until now, there is no available and effective therapeutic approach. Thus, it is necessary to search for care and adequate protection against the disease, especially for susceptible and vulnerable groups. Preconditioning, a well-known antioxidative stress and anti-inflammatory approach, is protective against many neurological age-related disorders. COVID-19 severity and morbidity have been observed in elderly patients. The aim of the present study is to elucidate the possible protective role of oxidative preconditioning in aged patients at high risk of developing severe COVID-19 complications.

An increase in AMPK/e-NOS signaling and attenuation of MMP-9 may contribute to remote ischemic perconditioning associated neuroprotection in rat model of focal ischemia.

Remote ischemic perconditioning (RIPerC) results in collateral enhancement and a reduction in middle cerebral artery occlusion (MCAO) induced ischemia. RIPerC likely activates multiple metabolic protective mechanisms, including effects on matrix metalloproteinases (MMPs) and protein kinases. Here we explore if RIPerC improves neuroprotection and collateral flow by modifying the activities of MMP-9 and AMPK/e-NOS. Age matched adult male Sprague Dawley rats were subjected to MCAO followed one hour later by RIPerC (3 cycles of 15 min ischemia). Animals were euthanized 24 h post-MCAO. Haematoxylin and Eosin (H&E) staining 24 h post-MCAO revealed a significant (p < 0.02) reduction in the infarction volume in RIPerC treated animals (24.9 ± 5.4%) relative to MCAO controls (42.5 ± 4.2, %). TUNEL staining showed a 42.6% reduction in the apoptotic cells with RIPerC treatment (p < 0.01). Immunoblotting in congruence with RT-PCR and Zymography showed that RIPerC significantly reduced MMP-9 expression and activity in RIPerC + MCAO group compared to MCAO group (218.3 ± 19.1% vs. 148.9 ± 12.05% (p < 0.01). Immunoblotting revealed that RIPerC was associated with a significant 2.5-fold increase in activation of p-AMPK compared to the MCAO group (p < 0.01) which was also associated with a significant increase in the e-NOS activity (p < 0.01). RIPerC resulted in reduction of infarction volume, decreased apoptotic cell death and attenuated MMP-9 activity. This together with the increased activity of p-AMPK and increase in p-eNOS may, in part explain the neuroprotection and sustained increase in blood flow observed with RIPerC following acute stroke.

Remote ischemic conditioning for the treatment of ischemic moyamoya disease.

AIMS: This study investigated the safety and efficacy of remote ischemic conditioning (RIC) on ameliorating the sequelae of ischemic moyamoya disease (iMMD). METHODS: A total of 30 iMMD patients underwent long-term RIC and were followed up at 0.5, 1, and 2 years for clinical outcomes, including frequency of stroke recurrence, Patient Global Impression of Change (PGIC) scale, peak systolic velocities (PSV), and cerebral perfusion. RESULTS: During the whole RIC treatment process, no RIC-related adverse event occurred. Only one of 30 patients suffered a onetime infarction (3.3%), and the ratios of acceptable PGIC were 88.2%, 64.3%, and 92.3% at 0.5, 1, and 2 years follow-up. Kaplan-Meier analysis showed the frequency of stroke recurrence was significantly reduced after RIC (P = .013). The frequency of TIA per week was 1.1 (0.6, 2.8) prior to RIC and 0.1 (0.0, 0.5) post-RIC (P < .01). Compared to baseline, PSV values were significantly reduced after RIC treatment (P = .002 at 0.5, P = .331 at 1, and P = .006 at 2 years). In patients undergoing perfusion studies, 75% obtained improvement on followed-up SPECT and 95% on followed-up PET maps. CONCLUSIONS: Remote ischemic conditioning may be beneficial on controlling iMMD-induced ischemic events, relieving symptoms, and improving cerebral perfusion, without incidence of complications in this case series.

The EUROpean and Chinese cardiac and renal Remote Ischemic Preconditioning Study (EURO-CRIPS CardioGroup I): A randomized controlled trial.

BACKGROUND: The potential protective effects of remote ischemic preconditioning (RIPC) on contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI) remain to be defined. METHODS AND RESULTS: A double blind, randomized, placebo controlled multicenter study was performed. Patients younger than 85years old, with a renal clearance of 30-60ml/min/1.73m2, who were candidates for PCI for all clinical indications except for primary PCI, were allocated 1:1 to RIPC or to standard therapy. The primary endpoint was incidence of CIN. The secondary endpoint was incidence of peri-procedural myocardial infarction (PMI). From February 2013 to April 2014, 3108 patients who were scheduled for coronary angiography were screened for the study. 442 fulfilled the inclusion criteria and 223 received PCI. These patients were randomized to sham RIPC (n=107) or treatment group (n=116). The only pre-specified subgroup of diabetic patients included 85 (38%) cases. RIPC significantly reduced CIN incidence in the overall population (12.1% vs. 26.1%, p=0.01, with a NNT=9) and in non-diabetic patients (9.2% vs. 25.0%, p=0.02), but showed no benefit in diabetics (16.7% vs. 28.2%, p=0.21). A trend for lower PMI was seen in the intervention arm (creatine kinase - muscle brain >5 URL; 8.4% vs. 16.4%, p=0.07; troponin T >5 URL; 27% vs. 38%, p=0.21). CONCLUSIONS: Remote ischemic preconditioning significantly reduces the incidence of acute kidney injury in non-diabetic patients undergoing PCI. Larger sample size is presumably needed to assess the effect of RIPC for patients with diabetes mellitus. Clinical Trial number:NCT02195726https://www.clinicaltrial.gov/.

Remote ischemic preconditioning does not prevent acute mountain sickness after rapid ascent to 3,450 m.

Remote ischemic preconditioning (RIPC) has been shown to protect remote organs, such as the brain and the lung, from damage induced by subsequent hypoxia or ischemia. Acute mountain sickness (AMS) is a syndrome of nonspecific neurologic symptoms and in high-altitude pulmonary edema excessive hypoxic pulmonary vasoconstriction (HPV) plays a pivotal role. We hypothesized that RIPC protects the brain from AMS and attenuates the magnitude of HPV after rapid ascent to 3,450 m. Forty nonacclimatized volunteers were randomized into two groups. At low altitude (750 m) the RIPC group (n = 20) underwent 4 × 5 min of lower-limb ischemia (induced by inflation of bilateral thigh cuffs to 200 mmHg) followed by 5 min of reperfusion. The control group (n = 20) underwent a sham protocol (4 × 5 min of bilateral thigh cuff inflation to 20 mmHg). Thereafter, participants ascended to 3,450 m by train over 2 h and stayed there for 48 h. AMS was evaluated by the Lake Louise score (LLS) and the AMS-C score. Systolic pulmonary artery pressure (SPAP) was assessed by transthoracic Doppler echocardiography. RIPC had no effect on the overall incidence (RIPC: 35%, control: 35%, P = 1.0) and severity (RIPC vs. CONTROL: P = 0.496 for LLS; P = 0.320 for AMS-C score) of AMS. RIPC also had no significant effect on SPAP [maximum after 10 h at high altitude; RIPC: 33 (SD 8) mmHg; controls: 37 (SD 7) mmHg; P = 0.19]. This study indicates that RIPC, performed immediately before passive ascent to 3,450 m, does not attenuate AMS and the magnitude of high-altitude pulmonary hypertension.NEW & NOTEWORTHY Remote ischemic preconditioning (RIPC) has been reported to improve neurologic and pulmonary outcome following an acute ischemic or hypoxic insult, yet the effect of RIPC for protecting from high-altitude diseases remains to be determined. The present study shows that RIPC, performed immediately before passive ascent to 3,450 m, does not attenuate acute mountain sickness and the degree of high-altitude pulmonary hypertension. Therefore, RIPC cannot be recommended for prevention of high-altitude diseases.

Effect of Hyperhomocysteinemia on Redox Balance and Redox Defence Enzymes in Ischemia-Reperfusion Injury and/or After Ischemic Preconditioning in Rats.

Increased level of homocysteine (hHcy) in plasma is an accompanying phenomenon of many diseases, including a brain stroke. This study determines whether hyperhomocysteinemia (which is a risk factor of brain ischemia) itself or in combination with ischemic preconditioning affects the ischemia-induced neurodegenerative changes, generation of reactive oxygen species (ROS), lipoperoxidation, protein oxidation, and activity of antioxidant enzymes in the rat brain cortex. The hHcy was induced by subcutaneous administration of homocysteine (0.45 µmol/g body weight) twice a day in 8 h intervals for 14 days. Rats were preconditioned by 5 min ischemia. Two days later, 15 min of global forebrain ischemia was induced by four vessel's occlusion. The study demonstrates that in the cerebral cortex, hHcy alone induces progressive neuronal cell death and morphological changes. Neuronal damage was associated with the pro-oxidative effect of hHcy, which leads to increased ROS formation, peroxidation of lipids and oxidative alterations of cortical proteins. Ischemic reperfusion injury activates degeneration processes and de-regulates redox balance which is aggravated under hHcy conditions and leads to the augmented lipoperoxidation and protein oxidation. If combined with hHcy, ischemic preconditioning could preserve the neuronal tissue from lethal ischemic effect and initiates suppression of lipoperoxidation, protein oxidation, and alterations of redox enzymes with the most significant effect observed after prolonged reperfusion. Increased prevalence of hyperhomocysteinemia in the Western population and crucial role of elevated Hcy level in the pathogenesis of neuronal disorders makes this amino acid as an interesting target for future research. Understanding the multiple etiological mechanisms and recognition of the co-morbid risk factors that lead to the ischemic/reperfusion injury and ischemic tolerance is therefore important for developing therapeutic strategies in human brain stroke associated with the elevated level of Hcy.

Effect of remote ischemic preconditioning on myocardial injury and inflammatory response induced by ablation for atrial fibrillation: A randomized controlled trial.

BACKGROUND: Remote ischemic preconditioning (RIPC) has been suggested to reduce postoperative release of cardiac and inflammatory markers in patients undergoing cardiac surgery. This study aimed to evaluate the effect of RIPC on nonischemic myocardial damage and inflammatory response in patients undergoing radiofrequency catheter ablation for paroxysmal atrial fibrillation (AF). METHODS: Seventy-two patients with drug-refractory paroxysmal AF undergoing radiofrequency catheter ablation were randomized into RIPC or control groups. RIPC (intermittent arm ischemia through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff) was performed once daily on 2 consecutive days before the ablation and immediately before ablation. Cardiac troponin-I (cTnI), high-sensitive C-reactive protein (hs-CRP), and interleukin (IL)-6 levels were measured before RIPC/sham RIPC, after the ablation, and 24 and 72h later. The early recurrence of atrial fibrillation (ERAF) in the two groups was observed over the subsequent 3months. RESULTS: Radiofrequency ablation resulted in a significant rise in cTnI, hs-CRP, and IL-6 in both groups, which persisted for 72h. The RIPC group showed a lower increase in cTnI (P<0.001), hs-CRP (P=0.003), and IL-6 (P=0.008) than the control and tended to have a lower risk of ERAF (hazard ratio [HR]=0.77, 95% confidence interval [CI]: 0.32-1.88). CONCLUSIONS: These results show that RIPC before ablation for paroxysmal AF significantly reduces the increase in cTnI, hs-CRP, and IL-6 associated with the procedure and results in a lower risk of ERAF. These findings suggest that RIPC could provide cardioprotection against nonischemic myocardial damage.

Protection of remote ischemic preconditioning against acute kidney injury: a systematic review and meta-analysis.

BACKGROUND: Remote ischemic preconditioning (RIPC) is a promising approach to preventing acute kidney injury (AKI), but its efficacy is controversial. METHODS: A systematic review of 30 randomized controlled trials was conducted to investigate the effects of RIPC on the incidence and outcomes of AKI. Random effects model meta-analyses and meta-regressions were used to generate summary estimates and explore sources of heterogeneity. The primary outcome was incidence of AKI and hospital mortality. RESULTS: The total pooled incidence of AKI in the RIPC group was 11.5 %, significantly less than the 23.3 % incidence in the control group (P = 0.009). Subgroup analyses indicated that RIPC significantly reduced the incidence of AKI in the contrast-induced AKI (CI-AKI) subgroup from 13.5 % to 6.5 % (P = 0.000), but not in the ischemia/reperfusion-induced AKI (IR-AKI) subgroup (from 29.5 % to 24.7 %, P = 0.173). Random effects meta-regression indicated that RIPC tended to strengthen its renoprotective effect (q = 3.95, df = 1, P = 0.047) in these trials with a higher percentage of diabetes mellitus. RIPC had no significant effect on the incidence of stages 1-3 AKI or renal replacement therapy, change in serum creatinine and estimated glomerular filtration rate (eGFR), hospital or 30-day mortality, or length of hospital stay. But RIPC significantly increased the minimum eGFR in the IR-AKI subgroup (P = 0.006) compared with the control group. In addition, the length of ICU stay in the RIPC group was significantly shorter than in the control group (2.6 vs 2.0 days, P = 0.003). CONCLUSIONS: We found strong evidence to support the application of RIPC to prevent CI-AKI, but not IR-AKI.

Molecular Mechanisms of Renal Ischemic Conditioning Strategies.

Ischemia-reperfusion injury is the leading cause of acute kidney injury in a variety of clinical settings such as renal transplantation and hypovolemic and/or septic shock. Strategies to reduce ischemia-reperfusion injury are obviously clinically relevant. Ischemic conditioning is an inherent part of the renal defense mechanism against ischemia and can be triggered by short periods of intermittent ischemia and reperfusion. Understanding the signaling transduction pathways of renal ischemic conditioning can promote further clinical translation and pharmacological advancements in this era. This review summarizes research on the molecular mechanisms underlying both local and remote ischemic pre-, per- and postconditioning of the kidney. The different types of conditioning strategies in the kidney recruit similar powerful pro-survival mechanisms. Likewise, renal ischemic conditioning mobilizes many of the same protective signaling pathways as in other organs, but differences are recognized.

Remote ischemic preconditioning prevents deterioration of short-term postoperative cognitive function after cardiac surgery using cardiopulmonary bypass: results of a pilot investigation.

OBJECTIVE: Remote ischemic preconditioning (RIPC) exerts neuroprotective effects in models of cerebral ischemia-reperfusion injury. The authors tested the hypothesis that RIPC decreases the incidence of postoperative delirium and prevents deterioration of short-term postoperative cognitive function in isoflurane-fentanyl-anesthetized patients undergoing cardiac surgery using cardiopulmonary bypass (CPB). DESIGN: Randomized, blinded, single-center pilot investigation. SETTING: Veterans Affairs Medical Center. PARTICIPANTS: Thirty age- and education-matched men≥55 years of age undergoing elective coronary artery or valve surgery using CPB. Fifteen nonsurgical patients also were enrolled. INTERVENTIONS: RIPC was produced after induction of anesthesia using 4 cycles of brief (5 minutes) upper extremity ischemia (tourniquet inflation to 200 mmHg) interspersed with 5-minute periods of reperfusion (tourniquet deflation). MEASUREMENTS AND MAIN RESULTS: The Intensive Care Delirium Screening Checklist was used to assess delirium before and each day after surgery for as many as 5 consecutive days. Recent verbal and nonverbal memory and executive functions were assessed before and 1 week after surgery using a standard neuropsychometric test battery or at 1-week intervals in nonsurgical controls. The Geriatric Depression and the Hachinski Ischemia scales were used to identify the presence of clinical depression and vascular dementia, respectively. No differences in delirium scores were observed between RIPC and control groups (p=0.54). Baseline neurocognitive scores were similar in patients with versus without RIPC in all 3 cognitive domains. Significant declines in performance on 2 nonverbal memory tests (figure reconstruction and delayed figure reproduction; p=0.001 and p=0.003, respectively) and 1 verbal memory test (delayed story recall; p=0.0004) were observed 1 week after surgery in patients who were not treated with RIPC. There were no changes in performance of measures of executive function in this group. In contrast, performance on all cognitive tests was unchanged after compared with before surgery in patients receiving RIPC. At least a 1-standard deviation decline from baseline in cognitive performance was detected in figure reconstruction, delayed figure reproduction, immediate story recall, and delayed story recall in patients who were not exposed to RIPC. The incidence of at least a 1-standard deviation decline in neuropsychometric tests was observed in significantly fewer (1 v 9; p<0.0001) patients with versus without RIPC treatment based on composite Z-scores. Overall cognitive performance after surgery was better in patients treated with versus without RIPC (p=0.002). Clinical depression and vascular dementia were not detected in either group. CONCLUSION: The results of this pilot investigation indicated that RIPC prevented deterioration of short-term postoperative cognitive function but were unable to detect any difference in delirium in isoflurane-fentanyl-anesthetized patients undergoing cardiac surgery using CPB.

Translation of remote ischaemic preconditioning into clinical practice.

Reduction of the burden of ischaemia-reperfusion injury is the aim of most treatments for cardiovascular and cerebrovascular disease. Although many strategies have proven benefit in the experimental arena, few have translated to clinical practice. Scientific and practical reasons might explain this finding, but the unpredictability of acute ischaemic syndromes is one of the biggest obstacles to timely application of novel treatments. Remote ischaemic preconditioning-which is a powerful innate mechanism of multiorgan protection that can be induced by transient occlusion of blood flow to a limb with a blood-pressure cuff-could be close to becoming a clinical technique. Several proof-of-principle and clinical trials have been reported, suggesting that the technique has remarkable promise. We examine the history, development, and present state of remote preconditioning in cardiovascular disease.

The year in cardiothoracic and vascular anesthesia: selected highlights from 2008.

The 2008 highlights in cardiovascular and thoracic anesthesia include the ultimate departure of aprotinin from clinical practice. However, a new antihypertensive drug, clevidipine, was approved for perioperative control of hypertension. There were also advances in pharmacologic myocardial conditioning with agents such as cyclosporine, sodium nitroprusside, and levosimendan. Furthermore, ischemic preconditioning appears ready for testing in large clinical trials designed to improve ischemic outcomes after cardiac surgery. With regard to transfusion, a landmark study suggests that transfused red blood cells stored for >2 weeks may significantly worsen major outcome after cardiac surgery. Furthermore, a second study suggests that relative rather than absolute hemoglobin reduction significantly determines adverse outcomes after cardiac surgery. These studies may greatly affect future transfusion guidelines. Left-sided valve replacement has been revolutionized by transcatheter technology, which progressed significantly in 2008. Important advances in percutaneous coronary intervention included drug-eluting bioabsorbable stents and further insights into the clinical consequences of platelet resistance. These 2008 themes represent a sampling of the total highlights for the year. Many of the advances not covered have been reviewed and discussed in the literature review sections of the Journal in 2008.

Transient ischemic attacks before ischemic stroke: preconditioning the human brain? A multicenter magnetic resonance imaging study.

BACKGROUND AND PURPOSE: We investigated whether transient ischemic attacks (TIAs) before stroke can induce tolerance by raising the threshold of tissue vulnerability in the human brain. METHODS: Sixty-five patients with first-ever ischemic territorial stroke received diffusion- and perfusion-weighted MRI within 12 hours of symptom onset. Epidemiological and clinical data, lesion volumes in T2, apparent diffusion coefficient (ADC) maps and perfusion maps, and cerebral blood flow and cerebral blood volume values were compared between patients with and without a prodromal TIA. RESULTS: Despite similar size and severity of the perfusion deficit, initial diffusion lesions tended to be smaller and final infarct volumes were significantly reduced (final T2: 9.1 [interquartile range, 19.7] versus 36.5 [91.2] mL; P=0.014) in patients with a history of TIA (n=16). This was associated with milder clinical deficits. CONCLUSIONS: The beneficial effect of TIAs on lesion size in ADC and T2 suggests the existence of endogenous neuroprotection in the human brain.

[Neuroprotection in brain tumors. Good sense or nonsense from the pathophysiological viewpoint?]. / Die Neuroprotektion bei Hirntumoren. Sinn oder Unsinn aus pathophysiologischer Sicht?

The hemodynamic and metabolic state of peritumoral brain tissue is not well understood, especially with subtotal or total, extraluminal compression of the carotid artery or other main intracranial vessels of the central nervous system. Possibly, parallels can be drawn from the knowledge in chronically malperfused brain tissue of atherosclerotic disease in sub- or nearly total stenosis of the internal carotid artery. From this point of view, it seems that the CBF/CBV quotient and oxygen extraction rate represent an additional diagnostic method-if needed in combination with the well-established balloon occlusion test-to help to better characterize the grade of still viable peritumoral brain tissue. The therapeutic strategy for possible pharmacological neuroprotection should be related to these parameters. It remains a matter of debate whether this clinical phenomenon will be one of the therapeutic domains influenced by ischemic preconditioning in the near-future.