Conditioning medicine最新文献

New treatments are needed to prevent adverse left ventricular remodelling following acute myocardial infarction (AMI), in order to prevent heart failure and improve clinical outcomes following AMI. Remote ischemic conditioning (RIC) using transient limb ischemia and reperfusion has been reported to reduce myocardial infarct (MI) size in AMI patients treated by primary percutaneous coronary intervention, and whether it can improve clinical outcomes is currently being investigated. Interestingly, repeated daily episode of limb RIC (termed 'chronic remote ischemic conditioning', or CRIC) has been shown in experimental and clinical studies to confer beneficial effects on post-AMI cardiac remodelling and chronic heart failure. In addition, the beneficial effects of CRIC extend to vascular function, peripheral arterial disease and stroke. In this review article, we focus on the therapeutic potential of CRIC as a strategy for cardiovascular protection and for improving clinical outcomes in patients with cardiovascular disease.

Hibernating mammals exhibit an innate physiological ability to withstand dramatic fluctuations in blood flow that occurs during hibernation and arousal or experimental models of ischemia reperfusion without significant damage. These innate adaptations are of significance particularly to organs that are highly susceptible to energy deprivation, such as the brain and the heart. Among vertebrates, the arctic ground squirrel (AGS) is a species that tolerates ischemic/anoxic insult. During the process of entering hibernation, a state of prolonged torpor, the AGS undergoes a profound decrease in respiratory rate, heart rate, blood flow, cerebral perfusion, and body temperature (Tb). The reduced level of blood flow during torpor resembles an ischemic state, albeit without energy deficit. During the process of arousal or emergence from torpor, however, when Tb, respiratory rate, heart rate, and blood flow rapidly returns to pre-torpid levels, the rapid return of cerebral blood flow mimics aspects of reperfusion such as is seen after stroke or cardiac arrest. This sublethal ischemic/reperfusion insult experienced by AGS during the process of arousal may precondition AGS to tolerate otherwise lethal ischemic/reperfusion injury induced in the laboratory. In this review, we will summarize some of the mechanisms implemented by mammalian hibernators to combat ischemia/anoxia tolerance.

Mitochondrial dysfunction is regarded as one of the major causes of neuronal injury in age-associated neurodegenerative diseases and stroke. Mitochondrial dysfunction leads to increased reactive oxygen species production, causing mitochondrial DNA mutations, which then results in pathological conditions. Negative conditioning of mitochondrial dysfunction via pharmacological inhibition, phytochemicals, and dietary restriction serve as an avenue for therapeutic intervention to improve mitochondrial quality and function. Here, we focus primarily on mitochondrial biology, evidence for mitochondrial dysfunction in neurodegenerative conditions such as dementia and stroke, and the possibility of using negative conditioning to restore or preserve mitochondrial function in these diseases.

Ischemic conditioning induces an endogenous protective mechanism that allows organisms to develop resistance to subsequent insults. The conditioning effect occurs across organs and species. Recently, much attention has been given to remote ischemic limb conditioning due to its non-invasive nature and potential therapeutic applications. While tolerance is induced at the primary injury site (e.g. the heart in cardiac ischemia and the brain in stroke), the site of conditioning application is away from the target organ, suggesting the protective factors are extrinsic in nature rather than intrinsic. This review will focus on the peripheral factors that account for the induction of tolerance. Topics of particular interest are blood flow changes, peripheral neural pathways, humoral factors in circulation, and the peripheral immune system. This review will also discuss how conditioning may negatively affect metabolically compromised conditions, its optimal dose, and window for therapy development.

Hypertrophic cardiomyopathy (HCM) is one of the most commonly inherited cardiac disorders that manifests with increased ventricular wall thickening, cardiomyocyte hypertrophy, disarrayed myofibers and interstitial fibrosis. The major pathophysiological features include, diastolic dysfunction, obstruction of the left ventricular outflow tract and cardiac arrhythmias. Mutations in genes that encode mostly for sarcomeric proteins have been associated with HCM but, despite the abundant research conducted to decipher the molecular mechanisms underlying the disease, it remains unclear as to how a primary defect in the sarcomere could lead to secondary phenotypes such as cellular hypertrophy. Mounting evidence suggests energy deficiency could be an important contributor of disease pathogenesis as well. Various animal models of HCM have been generated for gaining deeper insight into disease pathogenesis, however species variation between animals and humans, as well as the limited availability of human myocardial samples, has encouraged researchers to seek alternative 'humanized' models. Using induced pluripotent stem cells (iPSCs), human cardiomyocytes (CMs) have been generated from patients with HCM for investigating disease mechanisms. While these HCM-iPSC models demonstrate most of the phenotypic traits, it is important to ascertain if they recapitulate all pathophysiological features, especially that of energy deficiency. In this review we discuss the currently established HCM-iPSC models with emphasis on altered energetics.

Earlier studies established that ischemic tolerance can be induced in the brain using various strategies. An earlier study demonstrated that preconditioning with the toll-like receptor 9 ligand, CpG oligodeoxynucleotides (ODN), protects the brain against ischemic damage. To increase the potential translational value of the previous study, the goal of the present study was to replicate this earlier finding in a different animal cohort at a different site. In addition to these replication studies, following the Stroke Treatment Academic Industry Roundtable (STAIR) guidelines, we also conducted studies to evaluate the protective effect of CpG-ODN 1826 preconditioning on cerebral ischemic damage in ovariectomized (Ovx) female animals. Young male and female mice were treated with CpG-ODN 1826 or control ligand 3 days prior to the induction of transient (60 min) cerebral ischemia using a middle cerebral artery occlusion (MCAO) model. Infarct size was evaluated at ~24 h post-MCAO. We were able to replicate earlier findings that preconditioning with a low dose (20 μg/mouse) of CpG-ODN 1826 was able to lower cerebral ischemic damage in young male mice. However, we did not see any protective effect of low dose CpG-ODN 1826 preconditioning against cerebral ischemic damage in young Ovx female mice. Our study independently confirms the protective effect of CpG-ODN 1826 in inducing cerebral ischemia tolerance in male but not in Ovx female mice. Our study also demonstrates the feasibility of conducting such replication studies in rodent models of transient stroke.

During the premenopausal phase of a woman's life, estrogen naturally protects against ischemic brain damage and its debilitating consequence of cognitive decline. However, the decline in estrogen at menopause exponentially increases a women's risk for cerebral ischemia and its severity. Supplementation of estrogen during menopause is the most logical solution to abate this increased risk for cerebral ischemia; however, continuous therapy has proven to be contraindicative. Studies from our laboratory over the past decade have shown that a single bolus or long-term periodic 17β-estradiol treatment(s) two days prior to ischemia mimics ischemic preconditioning-conferred protection of the brain in ovariectomized or reproductively senescent female rats. These studies also demonstrated that 17β-estradiol-induced preconditioning (EPC) requires estrogen receptor (ER)-subtype beta (ER-β) activation. ER-β is expressed throughout the brain, including in the hippocampus, which plays a key role in learning and memory. Because periodic activation of ER-β mitigates post-ischemic cognitive decline in ovariectomized female rats, it can be surmised that EPC has the potential to reduce post-ischemic damage and cognitive decline in females. Estrogens are key anti-inflammatory agents; therefore this review discusses the effects of EPC on the inflammasome. Furthermore, as we now clearly know, the brain acts differently in males and females. Indeed, neurodegenerative diseases, including cerebral ischemia, and pharmacological drugs affect males and females in different ways. Thus, inasmuch as the National Institutes of Health and the Stroke Treatment Academic Industry Roundtable (STAIR) consortium mandate inclusion of female experimental animals, this review also discusses the need to close the gap in our knowledge in future studies of EPC in female animal models of cerebral ischemia.

Brain injury in the perinatal period occurs in many clinical settings, e.g. hypoxic-ischemic encephalopathy (HIE) in term infants, neonatal stroke, encephalopathy of prematurity, and infections. These insults often result in life-long disabilities including cerebral palsy, cognitive deficits, visual dysfunction, hearing impairments, and epilepsy. However, the success of clinical implementation of a broad array of potential neuroprotective strategies tested experimentally has been limited with the exception of therapeutic hypothermia (TH) used within hours of birth in term human babies with mild to moderate HIE. There is an extensive search for adjuvant therapeutic approaches to enhance the outcomes. One strategy is to modify susceptibility in the developing CNS by means of preconditioning or postconditioning using sublethal stress. The pre-clinical and clinical literature has shown that CNS immaturity at the time of ischemic insult plays a central role in the response to injury. Thus, better understanding of the molecular regulation of the endogenous vulnerability of the immature brain is needed. Further, the use of sublethal stressors of different origin may help shed light on mechanistic similarities and distinctions beween conditioning strategies. In this review we discuss the mechanisms of protection that are achieved by an interplay of changes on the systemic level and brain level, and via changes of intracellular and mitochondrial signaling. We also discuss the barriers to improving our understanding of how brain immaturity and the type of insult-hypoxic, ischemic or inflammatory-affect the efficacy of conditioning efforts in the immature brain.

Ischemic heart disease (IHD) is one of the leading causes of death and disability worldwide. Platelets, as the main regulators of hemostasis, are major players in acute myocardial ischemia/reperfusion injury (IRI). Additionally, platelets are modified by endogenous cardioprotective strategies such as ischemic preconditioning, postconditioning, and remote ischemic conditioning. In this article, we provide an overview of the functionional role of platelets in acute myocardial IRI, and highlight their potential as targets for cardioprotection to improve health outcomes in patients with IHD.

Acute myocardial infarction (AMI) and the heart failure (HF) that often results are among the leading causes of death and disability in the world. As such, novel strategies are required to protect the heart against the detrimental effects of acute ischemia/reperfusion injury (IRI), in order to reduce myocardial infarct (MI) size and prevent the onset of HF. The endogenous cardioprotective strategy of remote ischemic conditioning (RIC), in which cycles of brief ischemia and reperfusion are applied to a tissue or organ away from the heart, has been reported in experimental studies to reduce MI size in animal models of acute IRI. In the clinical setting, RIC can be induced by simply inflating and deflating a cuff placed on the upper arm or thigh to induce brief cycles of ischemia and reperfusion, a strategy which has been shown to reduce MI size in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PPCI). The results of the ongoing CONDI2/ERIC-PPCI trial are eagerly awaited, and will provide definitive answers with regards to the cardioprotective effect and clinical outcome benefits of RIC in STEMI.