Multi-organ Protection Research Articles

The role of Irisin in multiorgan protection.

Physical exercise is an effective strategy for improving human health. Various organs, including the heart, lung and kidney, can benefit from exercise. However, the underlying molecular mechanisms by which exercise protects organs remain unknown. Irisin, a myokine secreted from muscle in response to exercise, has attracted increased attention from researchers. The role of irisin in multiorgan protection has been gradually revealed, and this muscle-derived circulating factor is regarded as an essential bridge linking exercise and organ health. The mechanisms by which irisin protects diverse organs are different. Here, we review the research progress on the multiorgan protective effects of irisin and discuss the underlying molecular mechanisms.

The Controversy on the Role of ACE2 Receptor in COVID-19 Infection: The Protective Shift toward the ACE2 Axis

Background: Angiotensin-converting enzyme 2 (ACE2) is recognized as the main cellular receptor for the new coronavirus, SARS-CoV-2, that facilitates its entry into the host target cell, leading to the fatal viral infection, coronavirus disease 2019 (COVID-19). Thus, it is considered as a main therapeutic target in the SARS-CoV-2 infection. The dual role of ACE2 as a gate for SARS-CoV-2 virus and as a part of lung and multi-organ protection has built a scientific debate that affects the choice of treatments used against COVID-19 patient. ACE2 inhibitors like anti-ACE2 antibodies were first introduced as therapeutic solutions that, theoretically, would decrease the availability of target molecules for SARS-CoV-2 by downregulating ACE2 expression. However, animal studies showed that ACE2 upregulation acts as a counterbalance to the hypertensive pro-inflammatory angiotensin I-converting enzyme (ACE) in the renin–angiotensin system (RAS) and results in a protective role against acute lung injury – a fatal consequence of the disease. The current study tests the effect of ACE2-activating treatments against the outcome of genetic variations in the population that have ACE2-upregulatory effects.
 Conclusion Despite its role as a receptor for the SARS-CoV-2 virus, experimental studies and the genetic polymorphisms in populations that have ACE2 upregulation revealed a protective role against COVID-19 infection.
 
 Key words: ACE2 ACE COVID-19 treatments genetic variations

Systems pharmacological study illustrates the immune regulation, anti-infection, anti-inflammation, and multi-organ protection mechanism of Qing-Fei-Pai-Du decoction in the treatment of COVID-19

BackgroundThe traditional Chinese medicine (TCM) formula Qing-Fei-Pai-Du decoction (QFPDD) was the most widely used prescription in China's campaign to contain COVID-19, which has exhibited positive effects. However, the underlying mode of action is largely unknown. PurposeA systems pharmacology strategy was proposed to investigate the mechanisms of QFPDD against COVID-19 from molecule, pathway and network levels. Study design and methodsThe systems pharmacological approach consisted of text mining, target prediction, data integration, network study, bioinformatics analysis, molecular docking, and pharmacological validation. Especially, we proposed a scoring method to measure the confidence of targets identified by prediction and text mining, while a novel scheme was used to identify important targets from 4 aspects. Results623 high-confidence targets of QFPDD's 12 active compounds were identified, 88 of which were overlapped with genes affected by SARS-CoV-2 infection. These targets were found to be involved in biological processes related with the development of COVID-19, such as pattern recognition receptor signaling, interleukin signaling, cell growth and death, hemostasis, and injuries of the nervous, sensory, circulatory, and digestive systems. Comprehensive network and pathway analysis were used to identify 55 important targets, which regulated 5 functional modules corresponding to QFPDD's effects in immune regulation, anti-infection, anti-inflammation, and multi-organ protection, respectively. Four compounds (baicalin, glycyrrhizic acid, hesperidin, and hyperoside) and 7 targets (AKT1, TNF-α, IL6, PTGS2, HMOX1, IL10, and TP53) were key molecules related to QFPDD's effects. Molecular docking verified that QFPDD's compounds may bind to 6 host proteins that interact with SARS-CoV-2 proteins, further supported the anti-virus effect of QFPDD. At last, in intro experiments validated QFPDD's important effects, including the inhibition of IL6, CCL2, TNF-α, NF-κB, PTGS1/2, CYP1A1, CYP3A4 activity, the up-regulation of IL10 expression, and repressing platelet aggregation. ConclusionThis work illustrated that QFPDD could exhibit immune regulation, anti-infection, anti-inflammation, and multi-organ protection. It may strengthen the understanding of QFPDD and facilitate more application of this formula in the campaign to SARS-CoV-2.

Possible Use of Ganoderma Mushroom Extracts for the Treatment of Some Chronic Risk Factors Associated with Severe Covid-19

The novel coronavirus (SARS-CoV-2) emerged in Wuhan, China in December 2019 causing the coronavirus disease 2019 (COVID-19). The disease has caused a pandemic that had disrupted social and economic life globally. Intense research is ongoing to understand the nature of the virus and pathogenesis as well as the development of drugs and vaccines. Ample evidence suggests that the elderly people, those with pre-existing chronic medical conditions, such as lung disease, heart disease, diabetes, obesity, chronic kidney disease, compromised immunity and even men may be at higher risk of serious illness and intensive care. The virus tends to trigger the over-production of pro-inflammatory cytokines, which results in multiorgan damage, resulting in death. Following this review, we proposed the use of Ganoderma mushroom extracts, which have certain properties relevant to the management of COVID-19 complications including anti-inflammatory, antiviral, immune modulatory, and antioxidant, anti-aging and multiorgan protection. Most of this research has been done on rodent models with few clinical trials. Since, the mushroom is generally regarded as safe (GRAS) and have been used for centuries in Asian traditional medicine, we recommend the use of this mushroom in the management of the disease including as active ingredients in COVID-19 drugs, and alternatives to synthetic drugs, health supplements, adjuvant therapy or functional foods.

Organ-Protective Effects and the Underlying Mechanism of Dexmedetomidine.

Dexmedetomidine (DEX) is a highly selective α2 adrenergic receptor (α2AR) agonist currently used in clinical settings. Because DEX has dose-dependent advantages of sedation, analgesia, antianxiety, inhibition of sympathetic nervous system activity, cardiovascular stabilization, and significant reduction of postoperative delirium and agitation, but does not produce respiratory depression and agitation, it is widely used in clinical anesthesia and ICU departments. In recent years, much clinical study and basic research has confirmed that DEX has a protective effect on a variety of organs, including the nervous system, heart, lungs, kidneys, liver, and small intestine. It acts by reducing the inflammatory response in these organs, activating antiapoptotic signaling pathways which protect cells from damage. Therefore, based on wide clinical application and safety, DEX may become a promising clinical multiorgan protection drug in the future. In this article, we review the physiological effects related to organ protection in α2AR agonists along with the organ-protective effects and mechanisms of DEX to understand their combined application value.

Repeated Remote Ischemic Conditioning Reduces Doxorubicin-Induced Cardiotoxicity

ObjectivesThis study investigated the cardioprotective effect of repeated remote ischemic preconditioning (rRIC) on doxorubicin-induced cardiotoxicity in mice. BackgroundDoxorubicin is an effective chemotherapeutic agent for a wide range of tumor types but its use and dosing are limited by acute and chronic cardiotoxicity. Remote ischemic conditioning (RIC) is cardioprotective in multiple cardiovascular injury models, but the effectiveness of rRIC in doxorubicin-induced cardiotoxicity has not been fully elucidated. MethodsrRIC was performed on mice before and after doxorubicin administration. Cardiac function was assessed by echocardiography and myocardial biology was tested by molecular approaches. ResultsDoxorubicin administration induced acute cardiotoxicity, as indicated by reduced cardiac function, reduced myocyte cross-section area and increased extracellular collagen deposition, increased circulating cardiac muscle damage markers, and decreased heart weight. Doxorubicin also adversely affected other organs, including the kidney, liver, and spleen, as evaluated by circulating markers or organ weight loss. rRIC not only abrogated doxorubicin-induced cardiotoxicity (left ventricular ejection fraction, doxorubicin 47.5 ± 1.1%, doxorubicin + rRIC 51.6 ± 0.7%, p = 0.017), but also was associated with multiorgan protection. Within the myocardium, rRIC attenuated doxorubicin-induced cardiomyocyte apoptosis, reduced inflammation, and increased autophagy signaling. ConclusionsrRIC may be a promising approach to reduce doxorubicin-induced cardiotoxicity.

Multi-organ protection of ulinastatin in traumatic cardiac arrest model

BackgroundPost-cardiac arrest syndrome, which has no specific curative treatment, contributes to the high mortality rate of victims who suffer traumatic cardiac arrest (TCA) and initially can be resuscitated. In the present study, we investigated the potential of ulinastatin to mitigate multiple organ injury after resuscitation in a swine TCA model.MethodsTwenty-one male pigs were subjected to hemodynamic shock (40% estimated blood loss in 20 min) followed by cardiac arrest (electrically induced ventricular fibrillation) and respiratory suspension for 5 min, and finally manual resuscitation. At 5 min after resuscitation, pigs were randomized to receive 80,000 U/kg ulinastatin (n = 7) or the same volume of saline (n = 9) in the TCA group. Pigs in the sham group (n = 5) were not exposed to bleeding or cardiac arrest. At baseline and at 1, 3, and 6 h after the return of spontaneous circulation, blood samples were collected and assayed for tumor necrosis factor-alpha, interleukin 6, and other indicators of organ injury. At 24 h after resuscitation, pigs were sacrificed and apoptosis levels were assessed in samples of heart, brain, kidney, and intestine.ResultsOne pig died in the ulinastatin group and one pig died in the TCA group; the remaining animals were included in the final analysis. TCA and resuscitation caused significant increases in multiple organ function biomarkers in serum, increases in tumor necrosis factor-alpha, and interleukin 6 in serum and increases in the extent of apoptosis in key organs. All these increases were lower in the ulinastatin group.ConclusionUlinastatin may attenuate multiple organ injury after TCA, which should be explored in clinical studies.

Remote ischemic conditioning: a promising therapeutic intervention for multi-organ protection.

Despite decades of formidable exploration, multi-organ ischemia-reperfusion injury (IRI) encountered, particularly amongst elderly patients with clinical scenarios, such as age-related arteriosclerotic vascular disease, heart surgery and organ transplantation, is still an unsettled conundrum that besets clinicians. Remote ischemic conditioning (RIC), delivered via transient, repetitive noninvasive IR interventions to distant organs or tissues, is regarded as an innovative approach against IRI. Based on the available evidence, RIC holds the potential of affording protection to multiple organs or tissues, which include not only the heart and brain, but also others that are likely susceptible to IRI, such as the kidney, lung, liver and skin. Neuronal and humoral signaling pathways appear to play requisite roles in the mechanisms of RIC-related beneficial effects, and these pathways also display inseparable interactions with each other. So far, several hurdles lying ahead of clinical translation that remain to be settled, such as establishment of biomarkers, modification of RIC regimen, and deep understanding of underlying minutiae through which RIC exerts its powerful function. As this approach has garnered an increasing interest, herein, we aim to encapsulate an overview of the basic concept and postulated protective mechanisms of RIC, highlight the main findings from proof-of-concept clinical studies in various clinical scenarios, and also to discuss potential obstacles that remain to be conquered. More well designed and comprehensive experimental work or clinical trials are warranted in future research to confirm whether RIC could be utilized as a non-invasive, inexpensive and efficient adjunct therapeutic intervention method for multi-organ protection.

Dexmedetomidine attenuates cerebral ischemia/reperfusion injury in neonatal rats by inhibiting TLR4 signaling

ObjectiveThe sedative dexmedetomidine plays a role in multi-organ protection by inhibiting toll-like receptor (TLR) 4 expression in ischemia/reperfusion injury. The present study investigated whether the neuroprotective effects of dexmedetomidine could be blocked by the TLR4 agonist lipopolysaccharide.MethodsWe established a cerebral ischemia/reperfusion model in neonatal Sprague-Dawley rats through bilateral carotid artery occlusion for 20 minutes followed by a 2-hour reperfusion. Rats were assigned to four groups: Sham operation, ischemia/reperfusion, ischemia/reperfusion preceded by dexmedetomidine treatment (10 µg/kg), and ischemia/reperfusion preceded by dexmedetomidine (10 µg/kg) and lipopolysaccharide (500 µg/kg) treatments. Cerebral tissue injury was assessed by hematoxylin and eosin staining, and cerebral TLR4 expression was evaluated by real-time PCR and western blot.ResultsPretreatment with dexmedetomidine reduced ischemia-induced morphological changes in the hippocampal CA3 region and downregulated TLR4 expression, but these neuroprotective effects were partially blocked by co-treatment with the TLR4 agonist lipopolysaccharide.ConclusionOur results indicate that inhibition of cerebral TLR4 expression is related to the neuroprotective effects of dexmedetomidine in this neonatal rat cerebral ischemia/reperfusion model.

Dexmedetomidine preconditioning plays a neuroprotective role and suppresses TLR4/NF-κB pathways model of cerebral ischemia reperfusion

BackgroundDexmedetomidine has been reported to play an efficient role on multi-organ protection. Our study aims to investigate the neuroprotective of dexmedetomidine preconditioning on cerebral ischemic reperfusion (I/R) injury and investigate the underlining signaling mechanisms. MethodsCerebral I/R models were established with SD rats through middle cerebral artery occlusion (MCAO). After 2h of ischemia followed by 7days of reperfusion, the degree of cerebral tissue injury was detected by HE, Nissl and TUNEL staining. Glial fibrillary acidic protein (GFAP) positive and TNF-α positive cells were stained by immunohistochemistry and counted under microscope. TLR4, NF-κB and TIR-domain containing adapter-inducing interferon-β (TRIF) expression were detected by real time PCR and western blot. ResultsDexmedetomidine preconditioning markedly prevented the ischemia-induced cellular damage observed from HE and Nissl staining in hippocampus and cortex. Dexmedetomidine observably decreased the number of apoptotic cells in TUNEL staining. Besides, yohimbine could specifically suppress the protective effect of dexmedetomidine. GFAP expression was distinctly inhibited by dexmedetomidine preconditioning (10μg/kg, 20μg/kg) in cerebral ischemia area. Dexmedetomidine preconditioning inhibited the expression of TLR4 and NF-κB and increased that of TRIF. ConclusionThe results of this study suggest that dexmedetomidine preconditioning plays a neuroprotective role against I/R injury. Dexmedetomidine might suppress TLR4/NF-??B pathway and drive TLR4/TRIF signaling pathway to reduce the inflammatory injury.

Inhibition of NF-κB/TNF-α pathway may be involved in the protective effect of resveratrol against cyclophosphamide-induced multi-organ toxicity

Context: Cyclophosphamide (CyP), an efficient anticancer drug, may damage normal human cells. Resveratrol (RES), a natural polyphenol, has a diverse pharmacological properties.Objective: To test possible protective effect of RES on multi-organ damage caused by CyP.Materials and methods: RES (10 mg/kg/day) was administered orally for 8 days. In independent rat groups, CyP toxicity was induced via a single dose of 150 mg/kg i.p. 3 days before the end of experiment, with or without RES treatment.Results: Compared to control, CyP caused significant increase in organ-to-body weight ratios of heart, kidney and liver, with deterioration in their functional parameters; namely serum creatine kinase, blood urea nitrogen, creatinine, alanine aminotransferase and aspartate aminotransferase. CyP also caused distortion in these organs' histology, with significant tissue oxidative stress, manifested by decrease in reduced glutathione and catalase, as well as increase in malondialdehyde and nitric oxide levels. Furthermore, CyP caused multi-organ inflammatory effects as shown by increased tumor necrosis factor-α levels, as well as up-regulation of nuclear factor-κB expressions. Using RES concurrently with CyP restored heart, kidney and liver functional parameters, as well as their normal histology. RES also reversed oxidative stress, as well as inflammatory signs caused by CyP alone.Conclusions: RES may be beneficial adjuvant that confers multi-organ protection against CyP toxicity via antioxidant and anti-inflammatory mechanisms.

Understanding the Full Spectrum of Organ Injury Following Intrapartum Asphyxia.

Birth asphyxia is a significant global health problem, responsible for ~1.2 million neonatal deaths each year worldwide. Those who survive often suffer from a range of health issues including brain damage—manifesting as cerebral palsy (CP)—respiratory insufficiency, cardiovascular collapse, and renal dysfunction, to name a few. Although the majority of research is directed toward reducing the brain injury that results from intrapartum birth asphyxia, the multi-organ injury observed in surviving neonates is of equal importance. Despite the advent of hypothermia therapy for the treatment of hypoxic–ischemic encephalopathy (HIE), treatment options following asphyxia at birth remain limited, particularly in low-resource settings where the incidence of birth asphyxia is highest. Furthermore, although cooling of the neonate results in improved neurological outcomes for a small proportion of treated infants, it does not provide any benefit to the other organ systems affected by asphyxia at birth. The aim of this review is to summarize the current knowledge of the multi-organ effects of intrapartum asphyxia, with particular reference to the findings from our laboratory using the precocial spiny mouse to model birth asphyxia. Furthermore, we reviewed the current treatments available for neonates who have undergone intrapartum asphyxia, and highlight the emergence of maternal dietary creatine supplementation as a preventative therapy, which has been shown to provide multi-organ protection from birth asphyxia-induced injury in our preclinical studies. This cheap and effective nutritional supplement may be the key to reducing birth asphyxia-induced death and disability, particularly in low-resource settings where current treatments are unavailable.

Bentall with Total Arch Replacement using Long Elephant Trunk (TARLET) for Marfan’s Syndrome

Aortic arch surgery requires meticulous teamwork in the true perioperative sense. Planning and communication at all phases from preoperative evaluation through intraoperative management to postoperative care should be well coordinated between surgical anesthesia perfusion and intensive care unit teams. This case report discusses intraoperative management of a case of Marfanrsquos syndrome with anomalous right subclavian artery from the anesthesiologistrsquos perspective. Bentall with Total Arch Replacement using Long Elephant Trunk for Marfanrsquos syndrome with anomalous right subclavian artery was performed. Stanford type A dissection of the aorta extending down till the bifurcation can affect multi-organs system besides brain. An intraoperative strategy should aim multi-organ protection to avoid morbidity and mortality. Cerebral protection using retrograde and antegrade cerebral perfusion and systemic hypothermic circulatory arrest to protect multi organs made surgery and post-operative recovery uneventful.

The Effect of Holder Pasteurization on Activin A Levels in Human Milk.

There is evidence that mother's own milk is the best nutrient in terms of multiorgan protection and infection prevention. However, when maternal milk is scarce, the solution can be represented by donor milk (DM), which requires specific storage procedures such as Holder Pasteurization (HoP). HoP is not free from side effects since it is widely known that it causes qualitative/quantitative changes in milk composition, particularly in the protein content. Therefore, the aim of this study is to investigate the effects of HoP on Activin A, a neurobiomarker known to play an important role in the development and protection of the central nervous system. In 24 mothers who delivered preterm (n = 12) and term (n = 12) healthy newborns, we conducted a pretest/test study where the milk donors acted as their own controls. Each sample was divided into two parts: the first was frozen at -80°C (Group 1); the second was Holder-pasteurized before freezing at -80°C (Group 2). Activin A was quantified using an ELISA test. Activin A was detected in all samples. There were no significant differences (p > 0.05) between the two groups, also when the analysis was stratified for gestational age at delivery and milk maturation degree (p > 0.05, for both). The present findings on the absence of any side effects of HoP on the milk concentration of Activin A offer additional support to the efficacy of HoP in DM storage. Our data open up to further investigations on neurobiomarkers' assessment in human milk and their preanalytical stability according to storage procedures.

Early peritoneal lavage with ulinastatin improves outcome and enhances multi-organ protection in a model of severe acute pancreatitis.

The aim of this study was to investigate the effect of early peritoneal lavage with ulinastatin on the outcome of a rat model of severe acute pancreatitis (SAP). A total of 80 male Wistar rats were randomly divided into the following groups: Sham-operated (C), SAP model (M), saline lavage (SL), intravenous ulinastatin (IU), early ulinastatin lavage (EUL) and late ulinastatin lavage (LUL). Intraperitoneal lavage or injection were performed immediately subsequent to the establishment of the SAP model in groups SL, IU and EUL and 3 h later in group LUL. Intraperitoneal lavage with or without ulinastatin was performed for 3 h. The survival time of the rats in groups C, M, EUL and LUL was recorded over a 12-h period and the median survival time was calculated. At 3 h after the induction of SAP, histopathological analyses were performed and the biochemical parameters of groups C, M, SL, IU and EUL were assessed. Groups EUL and LUL exhibited an increased median survival time compared with Group M, with the survival time of the rats in group EUL markedly longer than that in the group LUL rats. Group SL, IU and EUL rats were found to have reduced plasma activities of amylase, lipase, aspartate transaminase and alanine transaminase, with the biggest change observed in the group EUL rats. Furthermore, the intervention in groups SL and EUL was more effective at reducing creatinine and urea levels than that in group IU. Rats in group EUL exhibited a greater inhibition of the SAP-induced increase in troponin T levels than rats in groups SL and IU. The pathological severity scores of the pancreas, liver, kidney and lung in group EUL were significantly lower than those in groups M and better than those in groups SL and IU. In conclusion, early intraperitoneal lavage with ulinastatin significantly improves the median survival time and protects multi-organ function in an SAP model.

The Role of Emulsified Isoflurane in Multi-Organ Protection

Aim of review: This review describes the multi-organ protective effects of emulsified isoflurane.Method: This review examines the recent experimental researches involving emulsified isoflurane-induced preconditioning and postconditioning in multiple organs.Recent findings: Emulsified isoflurane is a new formulation of isoflurane in lipid emulsion. It enables an intravenous, intraperitoneal injection or oral (rather than the traditional inhalation) route of administration for this anesthetic. Pharmacological preconditioning and postconditioning have been demonstrated to be the protective strategies in clinical settings for the high risk patients with various organ dysfunctions. In recent years, there has been increased interest in exploring the protective effect of emulsified isoflurane in multiple organs including heart, brain, kidney, liver and lung, providing potential approaches translating these convincing experimental conditioning effects to clinical practice.Summary: Emulsified isoflurane could exert strong organ-protective effects. With an understanding of its potential mechanisms, therapeutic approaches may be applied to the future organ-protective properties, transferring convincing experimental evidences into clinical therapies. Citation: Zhao-Yang Hu, Jin Liu. The role of emulsified isoflurane in multiorgan protection. J Anesth Perioper Med 2015; 2: 29-35. doi: 10.24015/JAPM.2015.0005This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

The prevalence of lithium-associated hyperparathyroidism in a large Swedish population attending psychiatric outpatient units.

This retrospective study determined the prevalence of lithium-associated hyperparathyroidism (LHPT) in 2 geographically defined, equivalent populations in Sweden, with no other selection bias. The medical journals of all patients receiving lithium treatment were examined specifically regarding their biochemistry: calcium, parathyroid hormone (PTH), creatinine, and vitamin D. The condition LHPT was defined biochemically. All patient data were noted, and the prevalence of the condition could thereby be calculated. A total of 423 patients were included (251 women and 172 men; 3:2), treated over a mean of 13.5 years (range, 1-46 years), aged 19 to 92. 77 patients (18%) were identified with LHTP whose median serum calcium was 2.55 mmol/L and PTH was 99 ng/L. A further 21% showed tendencies toward hypercalcemia. Forty-three percent had vitamin D insufficiency. Five patients (approximately 1%) had undergone parathyroidectomy. The prevalence of LHPT is high and often goes undetected. Vitamin D insufficiency is common as is polypharmacy. Surgery, for unclear reasons, has not been performed extensively, possibly because of limited knowledge of the underlying pathophysiology or surgery's significance. We present standard recommendations on patient management and suggest continual, specific follow-up including the monitoring of calcium, PTH, and vitamin D at least annually. Surgery should be considered with intention to improve psychiatric well-being and provide multiorgan protection.

A randomized pilot trial of remote ischemic preconditioning in heart failure with reduced ejection fraction.

BackgroundRemote ischemic preconditioning (RIPC) induced by transient limb ischemia confers multi-organ protection and improves exercise performance in the setting of tissue hypoxia. We aimed to evaluate the effect of RIPC on exercise capacity in heart failure patients.MethodsWe performed a randomized crossover trial of RIPC (4×5-minutes limb ischemia) compared to sham control in heart failure patients undergoing exercise testing. Patients were randomly allocated to either RIPC or sham prior to exercise, then crossed over and completed the alternate intervention with repeat testing. The primary outcome was peak VO2, RIPC versus sham. A mechanistic substudy was performed using dialysate from study patient blood samples obtained after sham and RIPC. This dialysate was used to test for a protective effect of RIPC in a mouse heart Langendorff model of infarction. Mouse heart infarct size with RIPC or sham dialysate exposure was also compared with historical control data.ResultsTwenty patients completed the study. RIPC was not associated with improvements in peak VO2 (15.6+/−4.2 vs 15.3+/−4.6 mL/kg/min; p = 0.53, sham and RIPC, respectively). In our Langendorff sub-study, infarct size was similar between RIPC and sham dialysate groups from our study patients, but was smaller than expected compared to healthy controls (29.0%, 27.9% [sham, RIPC] vs 51.2% [controls]. We observed less preconditioning among the subgroup of patients with increased exercise performance following RIPC (p<0.04).ConclusionIn this pilot study of RIPC in heart failure patients, RIPC was not associated with improvements in exercise capacity overall. However, the degree of effect of RIPC may be inversely related to the degree of baseline preconditioning. These data provide the basis for a larger randomized trial to test the potential benefits of RIPC in patients with heart failure.Trial RegistrationClinicalTrials.gov +++++NCT01128790

Ouabain—The Key to Cardioprotection?

Based on a wealth of mechanistic evidence supported by the fact that ouabain mimics the spleen-liver effect in this article, the hypothesis is established that the endogenous hormone ouabain not only mimics the effects of ischemic preconditioning but also may be an ideal drug for the prevention of ischemic diseases. Moreover, it is argued that the spleen-liver effect may represent a general protective mechanism for the protection of organisms against oxygen deficiency. Investigating the spleen-liver mechanism offers a new approach to decipher the secrets of ischemic conditioning. Preconditioning represents a basic mechanism to protect a wide variety of cells against stressful stimuli such as ischemia. The ability to undergo preconditioning is almost ubiquitous in tissues and is highly conserved across species. Reinvestigation of the "spleen-liver mechanism" will allow the study of metabolic inhibitors and hormone mimics that all could help to transform ischemic preconditioning into a cure of the epidemic ischemic heart disease. Ouabain mimics the effects of the spleen factor. Cardioprotection induced by ouabain is due to the activation of pathways that are also activated in ischemic preconditioning. Just like ischemic preconditioning, ouabain activates the reperfusion injury salvage kinase pathway. Activation of nuclear factor kappa B and other transcription factors contribute to the long lasting effects of ouabain. The endogenous hormone ouabain just like preconditioning offers multiorgan protection based on innate mechanisms, which warrants clinical investigation. Clinical studies with ouabain that correspond to current standards are warranted.

Conditioning Strategies Limit Cellular Injury?

Evaluation of multiorgan protection strategies against ischemic injury in humans is essential to improve quality of life and reduce mortality. Over the past 40 years a host of pharmacologic and non-pharmacologic interventions have been evaluated with the aim of limiting cell damage produced by ischemia-reperfusion injury. Different conditioning strategies, such as remote conditioning, are documented to mitigate ischemic injury in animal and human studies and may have remarkable clinical promise. However, successful clinical application of these interventions remains questionable since protection is known to be compromised in humans with comorbidities either with or without medications. Regardless, ongoing studies continue to examine the underlying mechanisms involved in this endogenous cytoprotective phenomenon to further its successful implementation in the clinical setting. In this review, we examine recent findings in support of remote conditioning stratagems for organ protection and their relevance for translation to clinical use.