HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: 296/6/H1705    most recent 00162.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Peart, J. N. Articles by Headrick, J. P. Search for Related Content PubMed PubMed Citation Articles by Peart, J. N. Articles by Headrick, J. P.

REVIEW

Clinical cardioprotection and the value of conditioning responses

Heart Foundation Research Centre, Griffith University, Queensland, Australia

Submitted 19 February 2009 ; accepted in final form 6 April 2009

ABSTRACT

Adjunctive cardioprotective strategies for ameliorating the reversible and irreversible injuries with ischemia-reperfusion (I/R) are highly desirable. However, after decades of research, the promise of clinical cardioprotection from I/R injury remains poorly realized. This may arise from the challenges of trialing and effectively translating experimental findings from laboratory models to patients. One can additionally consider whether features of the more heavily focused upon candidates could limit or preclude therapeutic utility and thus whether we might shift attention to alternate strategies. The phenomena of preconditioning and postconditioning have proven fertile in identification of experimental means of cardioprotection and are the most intensely interrogated responses in the field. However, there is evidence these processes, which share common molecular signaling elements and end effectors, may be poor choices for clinical exploitation. This includes evidence of age dependence, limiting efficacy in target aged or senescent hearts; refractoriness to conditioning stimuli in diseased myocardium; interference from a variety of relevant pharmaceuticals; inadvertent induction of these responses by prior ischemia or commonly used drugs, precluding further benefit; and sex dependence of protective signaling. This review focuses on these features, raising questions about current research strategies, and the suitability of these widely studied phenomena as rational candidates for clinical translation.

acute myocardial infarction; aging; cardiac ischemia; clinical translation; diabetes; obesity; preconditioning; postconditioning; reperfusion

The cardioprotection field was invigorated by the discovery of the Precon phenomenon in 1986 (155), revealing an unsurpassed ability to experimentally improve postischemic myocardial outcome (and revealing that even O₂- or I/R-sensitive species are able to mount effective adaptive responses). Since this discovery, of perhaps the most potent protective stimulus currently known, more than 3,000 published cardiovascular investigations have examined underlying mechanisms and assessed a means of harnessing Precon experimentally and clinically. Despite the elaboration of underlying signaling and development of a variety of triggers of this response in animal models, the therapeutic promise of Precon has not been realized. Mixed results have been acquired in clinical trials, and the extent of protection from cell death in cardiac patients is much less than in experimental models. More recently, powerful protection from Postcon was identified (244) and is also being actively studied (250 papers since that study) in the hope that this response, effective after ischemia itself, may be a more relevant candidate from a temporal perspective. Clinical Precon may have relatively limited application (in cardiac surgery, for example) given the need to pretreat hearts before ischemia, whereas Postcon possesses the more desirable feature of conferring benefit when implemented at or after reperfusion (although the window of opportunity for effective postischemic protection may be narrow).

Accumulating evidence indicates that Precon and Postcon act via archetypal mediators, sometimes referred to as reperfusion injury salvage kinase (RISK) elements, including phosphatidylinositol 3-kinase (PI3K), Akt, and PKC (48, 77). These may regulate downstream elements such as GSK3β and modify mitochondrial targets, including ATP-sensitive K⁺ (K_ATP) channels and the mitochondrial permeability transition pore (MPTP) to provide protection or to generate further signaling intermediates such as free radicals that participate in the cascade (48, 75, 77). Despite poor translation and mixed outcomes from trials, these conditioning responses remain the most intensely investigated candidates for cardioprotection, the hope being that mimetics (pharmacological or surgical in nature) or modulators of essential signaling/effectors will limit ischemic damage in patients. Given the mixed success of this endeavor over the past two decades, one might consider whether the focus on Precon (and more recently Postcon) remains the most rational approach or whether drawbacks inherent to these responses render them rather poor candidates for clinical exploitation. A number of recent commentaries and reviews (17, 79, 115) have addressed poor translation of experimental cardioprotection, with most attention drawn to issues in clinical trial and experimental design and rather less to the features of these responses that are highly relevant to the target population (59). It is these latter properties we review here and that argue for a shift in research strategy to specifically target aged and diseased hearts of both sexes to identify responses that might indeed be exploitable for cardioprotection in the target patient population.

Manipulating Ischemic Tolerance via Conditioning Responses

The extent of injury and thus the ultimate outcome from I/R depends on the duration and severity of the insult and on the intrinsic resistance of the tissue to O₂ deficit, energy/ionic/redox imbalances, and related features of I/R. The human myocardium is sensitive to ischemia, yet as in other mammals we possess adaptive processes that can transiently improve resistance to ischemic or hypoxic insult. Sublethal stressors, including cold, heat, exercise, calorie restriction, and transient periods of ischemia or hypoxia, can enhance cellular defense, limit age-related deterioration in cell function, and prolong lifespan. Precon is an example of such adaptation, documented in fish, birds, and mammals including humans (33, 64, 225).

Archetypal signaling in Precon/Postcon. The pathways triggering and mediating protection with Precon have been extensively studied, and a generalized signaling scheme has evolved, although features of these pathways remain controversial (48, 75, 77). Precon or Postcon stimuli (e.g., intermittent ischemia) enhance release of G-protein coupled receptor (GPCR) agonists such as opioids, adenosine, bradykinin, or catecholamines, which in turn activate prosurvival kinase or RISK paths (including PI3K/Akt, PKC, and the MAPKs ERK1/2 and p38) and inhibit prodeath paths (e.g., GSK3β), converging on mitochondrial targets such as K_ATP channels and the MPTP (48, 75, 77; Fig. 1). In addition to the debate regarding the roles of individual kinases (e.g., p38-MAPK) and other proteins (e.g., connexin-43), more global features of this protective scheme remain unclear, including whether the kinase cascade directly interacts with mitochondrial targets, for example, via a "signalosome" complex communicating signals from sarcolemmal receptor to mitochondrial membrane (177), or whether targets such as the MPTP are indirectly modulated through global shifts in oxidant levels and resultant modification of constituent proteins (32). Similarly, although most research focuses on the mitochondrial K_ATP channel, evidence has still been presented that the sarcolemmal channel contributes to cardioprotection (22, 71, 226), with recent work (144) indicating the channel may communicate with and affect mitochondria (144). A simplified signaling scheme for these responses is presented in Fig. 1. Note that Postcon involves GPCR engagement during reperfusion and that both stimuli may ultimately protect via RISK modulation and targeting of the MPTP in the reperfusion phase. The roles and timing of GPCR engagement may not be so clearcut, however. Work from Philipp et al. (171) supports involvement of adenosine receptors in Postcon, which may be sensitized during the preceding ischemia, facilitating their activation by agonists released with Postcon in reperfusion. Based on such a scheme, it remains feasible that Precon might trigger similar effects on GPCR functionality postischemia. Regardless of differences in initiation of these responses, they do appear to share common effector pathways during reperfusion (77).

View larger version (46K): [in this window] [in a new window]   Fig. 1. Generalized signaling scheme for Precon- and Postcon-dependent cardioprotection. Ischemic Precon triggers release/accumulation of G-protein coupled receptor (GPCR) ligands such as adenosine, bradykinin, and opioids. Respective receptor engagement leads to activation of ERK1/2, PKC (via phospholipase signaling with adenosine receptor agonism, for example), and the phosphatidylinositol 3-kinase (PI3K)/Akt cassette. Receptor tyrosine kinases may be involved, possibly via the EGF receptor) transactivation to activate PI3K/Akt. Activated Akt can phosphorylate multiple substrates, including endothelial nitrice oxide synthase (eNOS; to activate the PKG path via elevated cGMP), GSK3β [inactivating it and thus preventing its actions on mitochondrial permeability transition pore (MPTP) opening], and proteins regulating apoptosis (phosphorylating and inhibiting proapoptotic Bax and Bad and phosphorylating and activating anti-apoptotic Bcl-2 and also p70s6K, the latter inhibiting Bad). Activated PKG may not only contribute to PKC engagement and possibly inhibit the MPTP through activation of NO formation but target the sarcoplasmic reticulum protein phospholamban, promoting Ca2+ uptake to limit Ca2+ overload. The regulation and role of PKC are still debated, with a possible role for directly activated PKC, together with possible PKG-dependent phosphorylation of mitochondrial PKC, which in turn inhibits MPTP opening via mitochondrial KATP activation, alkalinization of the mitochondrial matrix, and generation of reactive oxygen species (ROS; the latter suggested to further activate PKC downstream of the KATP channel). Generation of reactive oxygen or nitrogen species, distal to mitochondrial KATP opening, may also trigger activation of kinases additional to PKC, including p38-MAPK and JAK/STAT. The ERK1/2 pathway may be crucial in inactivation of GSK3β (an effect that may also be activated by Akt). Ultimately, the opening of MPTP during early reperfusion is inhibited by these varied effects. Not shown are the sarcolemmal KATP channel and mitochondrial connexin-43, both of which have also been implicated in the Precon response, although their roles are incompletely defined. Components of this scheme also involved in Postcon are highlighted. The less well-studied Postcon response is thought to involve the PI3K/Akt pathway (although not all studies confirm this role) and ERK1/2, both modulating similar targets as in Precon. The mitochondrial KATP channel is again implicated, potentially limiting MPTP opening during reperfusion via undefined mechanisms. PKC may also play a role, although its location in the signaling cascade is unclear. There is also some evidence for a role for PKG in Postcon. Activation of these pathways in reperfusion may involve the actions of GPCR agonists including adenosine, with a possible sensitization of relevant receptors by prior ischemia. Another possibile trigger in Postcon involves transient acidosis in early reperfusion, contributing to kinase activation and additionally limiting early MPTP opening. mTOR, mammalian target of rapamycin.

Although a number of small clinical trials have been performed on forms of Precon and Postcon, such interventions have not been adopted in mainstream clinical practice. This may stem from a number of factors, including fundamental differences between the realities and limitations of the clinical environment vs. the controlled experimental conditions of the laboratory. As we will outline in further detail, these candidate interventions have also been studied in young healthy animal models, a scenario quite distinct from patients in need of cardioprotection (older subjects whose hearts and/or vessels are diseased). The limited number of trials of Precon/Postcon-based interventions to date has generated mixed findings regarding efficacy in patients.

Yellon et al. (238) in the first small clinical trial of Precon tested effects of two episodes of intermittent reperfusion in patients undergoing coronary artery bypass graft (CABG) surgery. They detected a 75% improvement in cardiac biopsy ATP content, supporting at least a metabolic protection. In a subsequent larger trial Illes and Swoyer (94) tested the effects of adjunctive ischemic Precon before cardioplegic arrest. Although no differences were evident in morbidity or mortality between groups, or in release of creatine kinase (CK), they detected a 32% improvement in functional outcome at 12 h postbypass. However, Jenkins et al. (100) did observe significant reductions in release of troponin T (by 80%) at 3 days post-CABG in an ischemic Precon cohort. These initial trials thus evidenced some benefit from forms of ischemic Precon. Nonetheless, there is also evidence Precon does not provide benefit over cardioplegia (37, 38) or as an adjunct to intermittent aortic cross-clamping during revascularization (167). Another study (170) acquired evidence of exaggeration of injury with ischemic Precon. Subsequent work by Teoh and colleagues (214, 215) indicates a superior protection with ischemic Precon vs. intermittent cross-clamping, cold cardioplegia, or pharmacological Precon, with 50–70% reductions in troponin T release compared with these interventions. Others present evidence that ischemic Precon is superior in limiting markers of cardiac cell damage vs. intermittent cross-clamp fibrillation (100, 207). Interestingly, trials of Precon stimuli in patients undergoing CABG with cold cardioplegia generally fail to alter enzyme markers of cardiac damage (37, 64, 233, 235, 236), although some detect reduced troponin I (101) or CK release (139).

Postcon has also been tested in humans in a small trial in patients reperfused within 6 h of myocardial infarction with four cycles of intermittent occlusion-reperfusion reduced CK release by 36% compared with the non-Postcon group (199). A retrospective analysis (41) of patients undergoing primary angioplasty also revealed a reduction in CK release in patients subjected to more than three balloon inflations vs. one to three inflations. In AMI, the application of Postcon stimuli 6–12 h after presenting with chest pain can reduce surrogate markers of infarction by 27% (237), 36% (143), or as much as 40–50% (216). Other small trials detect improvements in functional outcomes without alterations in markers of cell death (125).

Remote Precon, in which other tissues are subjected to intermittent I/R to indirectly promote recovery in the heart, has also been trialed in small studies. This stimulus has advantages over direct ischemic Precon, as it avoids added ischemic insult in the diseased heart and major vessels. Günaydin et al. (72) used a tourniquet around the right upper extremity of patients, which was inflated/deflated to affect 3-min periods of ischemia. They found no improvement in CK release but an elevation in lactate dehydrogenase levels and suggested an effect of remote Precon on anaerobic glycolysis. Subsequent trials support benefit from remote Precon in differing patient cohorts, including reductions in troponin T in pediatric patients (31) and 40–60% reductions in this marker at differing times in adults undergoing CABG (78), abdominal aortic aneurysm repair (7), and coronary stenting procedures (87).

Some of the drawbacks of ischemia as a Precon or Postcon stimulus may be limited by the use of pharmacological conditioning mimetics. Indeed, one of the aims of ongoing research into the molecular bases of these responses is to identify candidates for pharmacological manipulation. While Teoh et al. (214) acquired evidence of a superior effect of ischemic vs. pharmacological Precon, other support for benefit via conditioning pharmacomimetics has been acquired. Adenosine may play a key role in triggering cardioprotection with Precon and Postcon (77, 231), although it provides other beneficial effects that may be independent of these responses (166). Trials of adenosine as an adjunctive protective therapy have been successful in limiting postinfarct mortality (116), together with up to a 60% reduction in infarct vs. no treatment (182). Since adenosine was applied during ischemia and reperfusion, this protection may reflect Postcon rather than Precon effects. In the context of cardioplegic arrest, the adenocaine intervention (adenosine + lidocaine) for nondepolarizing preservation developed by Geoff Dobson (46) has proven very effective experimentally and in clinical trials. The IONA trial supports benefit from chronic K_ATP opener treatment (nicorandil) in patients with known coronary artery disease (95). On the other hand, Kitakaze et al. (113) in the J-WIND trial observed infarct limitation with atrial natriuretic peptide but not nicorandil in infarct patients undergoing reperfusion therapy. Again, as these agents were not present before ischemia, this action can be deemed more akin to a Postcon stimulus. It is interesting in this respect that the K_ATP opener failed to afford benefit, despite evidence for a role for this channel in both Precon and Postcon (48, 75, 77). On the other hand, other studies (96) do report some benefit with nicorandil under similar conditions.

Overall, clinical trials do offer evidence of some benefit from Precon- or Postcon-based therapies in certain clinical scenarios. However, evidence of infarct limitation is mixed, and such effects are generally much less than in experimental laboratory models. Reasons for these mixed responses are unclear, although as we discuss in more detail in subsequent sections, some of the intrinsic features of conditioning responses may be critical in limiting their efficacy and translation in the clinical environment. An added factor worth mentioning here is that the magnitude of benefit with cardioprotective stimuli may need to be very substantial before it is evident in reperfused myocardium. Early reperfusion alone (within 30–90 min) can limit infarction by 40–50% (152, 239). However, the outcomes with reperfusion vary widely, with salvage of >50% of at-risk myocardium in one out of two of AMI patients, while up to one out of four may still suffer >75% infarction despite effective reperfusion (152). The latter injury certainly argues for provision of adjunctive therapy, although only very potent responses would limit infarction to a goal of 20% of the effected ventricle (a threshold above which mortality and morbidity appear to rise; Ref. 152). Whether Precon or Postcon stimuli could independently affect this large reduction is not clear, and this may contribute to mixed efficacy in trials. Nonetheless, any graded reductions in infarction from 75 toward 20% should still improve outcome (while reductions below 20% may not further affect mortality). Moreover, early reperfusion remains unrealized in many cases: analysis of 27,000 US patients (27) and 3,000 hospital systems (232) documents means delays from symptom onset (or hospital arrival) to clinical reperfusion of 4–5 h, well outside the 30- to 90-min optimum for salvage and mortality reduction. Thus there remains a very good case for application of adjunctive protective therapy before or with reperfusion.

Age and Disease Dependence of Cardioprotection

It has been noted previously that protective strategies that fail in translation have historically been associated with inconsistent data regarding efficacy in experimental models (17). As we highlight below, there are key inconsistencies in observed efficacy of Precon- and Postcon-based interventions that should raise concern regarding their potential utility in patient populations. Unfortunately, there is a bias to publication of positive rather than negative findings in the scientific literature, which in turn may inadvertently bias views on the efficacy of a particular response. Our aim here is to play the role of "devils advocate" in promoting a critical appraisal of ongoing research strategies, presenting an overview of negative data relevant to the clinical applicability of Precon- and Postcon-based interventions. We suggest that poor clinical translation of conventional protective strategies may well reflect drawbacks inherent to Precon and Postcon, including age dependence and refractoriness in diseased patients (addressed here), interactions with common pharmaceuticals and environmental factors, and sex dependence (the latter addressed in subsequent sections).

Age dependence. A key problem with Precon responses, potentially mirrored in Postcon, is progressive loss of efficacy with age. Although this remains somewhat contentious, as some investigators do report preservation of Precon or related protection in aged hearts (23, 123, 138), the weight of evidence indicates that age reduces or abrogates Precon responses in humans (2, 12, 128, 136, 151, 159) and in animal models (1, 16, 50, 56, 85, 140, 186, 210, 211). Aging also inhibits protection via remote Precon (89), anesthetic Precon (197), in response to GPCR agonists such as adenosine (81, 173, 186, 231) or opioids (164, 165), and novel forms of Precon (82). Two recent studies (15, 174) also report that aging abrogates protection with Postcon. The negative influence of age on cytoprotection is not restricted to the cardiac system: aging impairs or eliminates Precon responses in brain (80, 184), liver (186, 190, 242), and platelets (173). Failure of these adaptive responses could be a general and integral component of the aging process, ultimately limiting the ability of tissues to adapt effectively to stress or withstand injurious insult (defining features of cellular senescence).

Despite a weight of evidence supporting age-dependent impairment of Precon, Postcon, and related stimuli, a number of investigations did detect preserved protective responses in aged myocardium. Loubani et al. (138) reported on effective Precon of aged human tissue, and Burns et al. (23) provided support for preserved Precon in aged sheep. In addition, the antiarrhythmic effects of Precon may be effective in aging rats (91). Additionally, Shinmura et al. (193) presented evidence of a preserved delayed Precon response in aged rats. Other work supports conservation of the Postcon effect: Lauzier et al. (126) reported preserved Postcon in the Senescence Accelerated Mouse Prone 8 model, while Dow et al. (47) presented evidence that the antiarrhythmic effects of Postcon are conserved in aged rats. Other experimental interventions reported to proffer protection in aged hearts include Na⁺/H⁺ exchange inhibition (14, 158), prolonged opioid treatment (164), PKC-activating peptide (119), PKC inhibition (120), adenosine treatment (123), and CRYAB and HSPB2 deficiency (13).

The reasons for the preservation of protective responses in some studies but not others is not readily apparent, although some research suggests that perhaps the threshold for effecting cardioprotection with Precon or Postcon stimuli is elevated, necessitating a greater stimulus to overcome downstream defects (15, 128, 186). This would be consistent with graded responses to Precon stimuli (107, 187) and could explain variable data regarding age and Precon: studies of more profound Precon stimuli may detect efficacy in older hearts, while those using lower subthreshold stimuli may not. However, other investigations (86) identifying age-related abnormalities in cardioprotection have found that an enhanced stimulus is unable to overcome these changes. This issue requires further investigation, as it is critical to understand the basis of failed protection if these responses are to be harnessed for elderly patients.

An impaired sensitivity to initiating stimuli, noted above, is in part consistent with evidence that failed cardioprotection involves impaired activation of signaling, particularly at the level of p38-MAPK (165) (Table 1). Abnormal cell signaling is also in agreement with studies in diseased hearts (70, 76) and with observations that increasing the amplitude of the trigger stimulus may generate protection in older hearts, for example, with additional (186) or longer (15) conditioning cycles or with enhanced protective GPCR expression (81). These latter studies confirm that protective machinery is still present in older hearts but appears ineffectively activated and harnessed. Investigators have unmasked other relevant aspects of impaired signaling. Tani and colleagues (208, 212) provided evidence of failed activation and translocation of PKC in aged hearts. Przyklenk et al. (172) have shown that age selectively alters the nature of protective PKC signaling, with Precon responses PKC dependent in young but not aged myocardium. Hunter et al. (92) have acquired evidence of a role for altered kinase activation and GSK3β regulation in age-related ischemic intolerance. Other evidence of a signaling basis to failed protection includes shifts in phosphatase activity that may alter kinase phosphorylation (57) and impaired expression of connexin-43 (16), a gap-junction protein thought to be involved in protective signaling (188). There are parallels between the aging effects on signaling and the effects of disease (outlined in the following sections) (Table 1). For example, elevations in phosphatases may also be involved in impaired protection with obesity (18), while ineffective activation of kinases is also detected in diabetes (70, 219). It is important to continue these investigations into protective responses and signaling in aged myocardium, as this may not only reveal more effective protective strategies for the target patient population but may also provide insights into the molecular basis of age-related changes in both physiology and the pathogenesis of heart disease. Even at the level of randomized clinical trials in acute coronary syndromes, there is underrepresentation of elderly subjects and women (130).

Influence of disease. A clinically useful cardioprotectant must be efficacious in diseased myocardium. Considerable evidence indicates that conventional responses derived from Precon and Postcon are negatively influenced by common conditions including diabetes, obesity, dyslipidemia, and possibly hypertrophy. Since diabetes and obesity are increasing in near epidemic proportions, are major risk factors for development of heart disease, and aggravate injury from ischemic insult, it is a decidedly negative feature for cardioprotective interventions to be sensitive to these conditions. The presence of such disease states, overlaid on an aged myocardial substrate, may render hearts insensitive to many conventional protective stimuli.

DIABETES. Ghosh et al. (65) demonstrated failed Precon in diabetic human myocardium and also in hearts with pathological reductions in the ejection fraction. Others demonstrated impairment of Precon-related responses in diabetic patients (127), consistent with experimental evidence of failed cardioprotection via Precon in diabetic animal models (42, 43, 110, 122, 141, 218). Responses to related or pharmacological stimuli are also impaired with diabetes, including anesthetic Precon (109, 209), opioid-mediated Precon (70, 175), and protection in response to heat stress (104), phosphodiesterase-5 inhibition (98), or via sphingolipid-dependent PKC modulation (73). Delayed or late Precon responses may also be eliminated (49).

The mechanistic basis of failed protection in diabetes has been investigated, with evidence that failure in human tissue arises from abnormalities in signaling, potentially upstream of PKC and p38-MAPK (76), consistent with impaired activation of p38-MAPK in aged mice (165). A signaling basis to failed protection in diabetic hearts is also consistent with decreased sensitivity of kinase signaling to Precon stimuli (219) and impaired activation of STAT3, Akt, and ERK1 with altered modulation of GSK3β (70). Additionally, there is evidence of K_ATP channel dysfunction (42, 43), mitochondrial dysfunction (76), excess accumulation of reactive oxygen species (109), impaired synthesis of stress-inducible heat shock protein (HSP) 70 (175), and impaired calcitonin gene-related peptide expression (140, 141). Overall, there is good evidence that some form of signaling dysfunction underlies poor protective efficacy in the diabetic myocardium. An obvious complicating factor is the inhibitory effect of hypoglycemic agents, particularly sulfonylureas that impair K_ATP channel activation (33, 90, 114, 189) and worsen cardiovascular outcomes (63). Curiously, ischemic Precon may also impair the benefit with K_ATP channel openers (28). Fortunately, some hypoglycemic drugs do not appear to exert these detrimental actions (114). Nonetheless, since hypoglycemic agents are not the primary cause of failed protection in diabetes, cardioprotection is unlikely to be restored solely through judicious choice of a hypoglycemic drug.

OBESITY. Obesity is increasing globally at alarming rates (doubling in both men and women in certain age groups in the last decade) and is one of the major risk factors for development of ischemic heart disease. Given common coexpression of obesity with other abnormalities, particularly other components of the so-called "metabolic syndrome" (glucose intolerance, hypertension, and dyslipidemia), it can be difficult to delineate the roles of individual disease constituents. Wagner et al. (224) have shown the loss of Precon in a rat model of established metabolic syndrome. In the ob/ob mouse, a leptin-deficient obesity model, cardiac benefit from Postcon is impaired (18), while there is also evidence of failed Precon in obese insulin-resistant rats (106). Similarly, the protective effects of other stimuli are impaired in obese animals (73).

The molecular basis of the detrimental influence of obesity is unclear, although again dysregulation of kinase signaling may be involved. Bouhidel et al. (18) reported failed activation of Akt, ERK1/2, and p70S6K1 in ob/ob mice, potentially involving enhanced expression of counteracting phosphatases. Similarly, Wagner et al. (224) acquired evidence of impaired ERK activation and failure to phosphorylate and inactivate GSK3β. Ineffective protection in obese insulin-resistant rats is associated with increased mitochondrial oxidant damage and impaired mitochondrial K_ATP channel activation (106). As in aging and diabetes, there appear to be abnormalities in the activation of protective kinase cascades and mitochondrial K_ATP channels in hearts from animals that are obese or suffer from the metabolic syndrome (Table 1). These similarities are suggestive of a common signaling dysfunction with age and disease, leading to poor tolerance and adaptation to injurious insult.

DYSLIPIDEMIA. The effect of atherosclerosis on dyslipidemia is equivocal, with opposing data acquired from different laboratories and in different models. Early evidence that hyperlipidemia might alter Precon responses arose from the study of Szilvássy et al. (206), where Precon was shown to be substantially inhibited in hypercholesterolemic rats. These investigators presented evidence that hyperlipidemia rather than resultant atherosclerosis is the key factor, since the effect was reversed by normalizing diet despite persistent atherosclerosis. Ferdinandy et al. (58) subsequently confirmed impaired Precon with hypercholesterolemia in the absence of atherosclerosis. The group also found that delayed protection with Precon was preserved despite elimination of the acute response, supporting selective inhibitory actions of hyperlipidemia. Ueda et al. (221) showed that hypercholesterolemia eliminated Precon in rabbits, an effect countered by treatment with a HMG-CoA reductase inhibitor (without altering plasma cholesterol substantially), while Koci et al. (117) detected impaired functional protection with Precon in cardiac muscle from hyperlipidemic rats. Kyriakides et al. (124) present evidence of failed ischemic Precon in hyperlipidemic patients, a dysfunction supported by the more recent study of Ungi et al. (222), who found both worsened ischemic injury and inhibition of Precon in hypercholesterolemic patients.

Despite these latter findings in humans, recent studies in animal models have generated mixed results regarding dyslipidemias and cardioprotection. While Giricz et al. (66) confirmed that hyperlipidemia eliminates protection with Precon in rats (an effect potentially related to dysregulation of matrix metalloproteinase-2), Jung et al. (105) and Kremastinos et al. (121) reported that hypercholesterolemia does not negate Precon in rabbits. Nonetheless, intrinsic tolerance to I/R was found to be reduced in the study of Jung et al. (105). Benefit from Precon is also evident in a genetic murine model (ApoE/LDLr knockouts on atherogenic diets) of atherosclerosis (132), and Iliodromitis et al. (93) detected preservation of Precon but failure of Postcon in hypercholesterolemic rabbits.

There is certainly a good theoretical basis for an influence of dyslipidemia on cardioprotection. Cell signaling is dependent on membrane makeup and function, which are sensitive to dietary lipids. Shifts in the makeup of lipid-rich caveolar domains may underlie age-dependent alterations in receptor signaling and cell function (163). Membrane makeup also dictates sensitivity to environmental factors and may govern gene expression for important regulatory elements (223). In this respect, hyperlipidemia has been shown to impair the expression of HSP70 (39). This protein may be important in tissue protection, and impaired expression is implicated in failed Precon in diabetes (175). Other factors potentially involved include reduced NO bioavailability (58, 88) and modification of caspase signaling and apoptosis (227). Overall, and despite ongoing controversy, the evidence does implicate a negative influence of hyperlipidemia on Precon and related protective responses.

HYPERTROPHY/HYPERTENSION. Ebrahim et al. (50) recently found that cardiac protection via Precon is impaired in aged hypertensive rats, involving the effects of both hypertension itself and of age. In other work, this group identified impaired cardioprotection with a GPCR stimulus (bradykinin) but preserved ischemic Precon in DOCA-salt hypertensive rat hearts (51). These findings are somewhat consistent with the earlier data of Reiss et al. (179), who showed that anesthetic Precon was also limited in larger or older hearts. Others (153) detected failed protection in hypertrophied myocardium. In contrast, there are also reports (24, 35, 157, 162, 198) of preserved protection in hypertrophy or hypertension, while others reported (178) enhanced protection in genetic hypertension. Related stimuli are reported to retain protective efficacy in hypertrophy (61, 84).

There is also mixed evidence regarding Precon in postinfarct remodeled myocardium. Miki et al. (150) found evidence of impaired Precon in remodeled hearts, although this was countered by more direct targeting of downstream mitochondrial K_ATP channels (again supporting a limitation in signaling between triggering receptors and downstream effectors). Delayed or late Precon may also fail in remodeled hearts (55). However, Lucchinetti et al. (142) and Feng et al. (54) observed effective anesthetic Precon in remodeled myocardium. Thus selective aspects of protective signaling may be altered in the remodeled heart, which may be relevant to clinical utility in subjects who have experienced prior infarction.

Some of the inconsistency regarding the influences of hypertrophy and hypertension may arise from the fact that stretch itself can trigger cardioprotection (74, 157). Thus the ultimate outcome may reflect a mix of pathological induction of Precon overlaid on potentially detrimental effects of hypertrophy itself. Certainly, the protective response in hypertrophied hearts may differ from that in nonhypertrophied tissue. Butler et al. (25) found that hypertrophy shifts STAT signaling involved in Precon, with an important STAT-3 dependence in hypertrophied but not normal hearts. As with aging, it is possible that the molecular basis of these responses changes substantially with disease. This may be problematic in the development of clinical interventions, since molecular research in healthy tissue may not at all reflect the nature of these responses in diseased hearts (Table 1).

Drug and Environmental Interactions

Pharmacological interactions. A third important drawback to Precon or Postcon is that the implicated triggers and signaling paths are sensitive to common pharmaceuticals. These agents have the capacity to either interfere with essential signaling or inadvertently trigger protection (both actions precluding additional benefit from subsequent or adjunctive therapy targeting the same processes). Protective Precon/Postcon pathways may suffer interference from agents commonly used in coronary care, including β-blockers, nonsteroidal anti-inflammatories, Ca²⁺ channel blockers, and hypoglycemic sulfonylureas (as already discussed above).

INHIBITORY INTERACTIONS. The most obvious negative interaction is via drugs blocking the mediation or triggering of cardioprotection. Again, the results are mixed in terms of the effects of different agents on experimental cardioprotection. A number of studies raise concerns regarding the possible inhibitory effects of nonsteroidal anti-inflammatories such as aspirin. Gross et al. (69) reported blockade of opioid-dependent protection with aspirin but not ibuprofen (which actually augmented the benefit), while Jancso et al. (99) found that aspirin eliminates delayed Precon. Shinmura et al. (192) reported that such inhibition may be dose dependent, with no effect of low doses used for antithrombotic or analgesic purposes, whereas high levels used for antirheumatic therapy did block delayed Precon. Thus although there is an inhibitory influence of aspirin, this might be reduced through choice of dose. Blockade of Ca²⁺ channels may also interfere with protection via Precon stimuli. Cain et al. (26) found that clinically used antagonists eliminate the Precon response in human myocardium, suggesting also that the detrimental effects of Ca²⁺ channel blockade on mortality (40) could stem from inhibition of intrinsic protective responses.

Both - and β-adrenoceptor blockade can interfere with cardioprotection via Precon. β-Adrenoceptors are themselves implicated in protection, with studies demonstrating induction of a Precon-like state after β-adrenoceptor agonism (169). This is congruent with observations of impaired cardioprotection in animals treated with β-adrenoceptor blockers (203). Complicating matters, β-adrenoceptor blockade may also be protective (60, 97, 203). It is thus difficult to isolate the effects of the blocking agent on cardioprotection, independently from effects on intrinsic resistance. The -adrenoceptor can also affect protection: Tomai et al. (217) acquired evidence of impaired Precon in patients treated with the -selective blocker phentolamine, supporting a role for -adrenoceptors in protecting human myocardium. It should be noted that issues of interference from different receptor blockers may be less of a concern than inhibitors of downstream signaling (as with aspirin, for example), since a clinically translated form of Precon or Postcon may well involve alternate or multiple GPCR stimuli or may target molecular events distal to receptor engagement.

INTERFERENCE FROM CONDITIONING "MIMETICS." In addition to drugs inhibiting Precon or Postcon responses, patients are often exposed to agents that may actually trigger the same signaling pathways, including anesthetics (54, 241), opioid-based analgesics (69, 164), and vasodilators (83, 103, 131). While such effects may provide acute benefit, they will simultaneously exclude further protection from therapy targeting Precon or Postcon mechanisms. Patients may additionally be exposed to prior sublethal ischemia before suffering AMI. Thus intrinsic Precon responses may already be endogenously triggered and/or have become refractory due to continued or frequent activation (both effects precluding added benefit from therapies targeting the same pathways). This possibility is supported by the work of Wu et al. (234), who found that coronary artery bypass patients who experienced angina 48 h before surgery were refractory to an ischemic Precon stimulus, whereas patients with angina 48 h before surgery responded to the same Precon stimulus.

The potential for this type of interaction is highlighted in Fig. 2, depicting postischemic functional recoveries of murine hearts that were untreated or received a mix of commonly applied agents (aspirin, morphine, and glyceryltrinitrate). The data show that these common drugs do trigger benefit, with ischemic Precon unable to provide added benefit in these hearts. Thus standard therapeutics already in place may induce the very protection one is seeking to trigger with conditioning-based intervention. From the perspective of clinical trials, which contrast effects of novel adjunctive therapy with placebo (i.e., best conventional treatment ± adjunctive cardioprotection), there may be no evidence of efficacy if ischemic patients have inadvertently been placed in a protected state via common pharmacotherapies or disease history. Best current practice may already confer the benefit of conditioning responses, and extensive development of conditioning-based therapies may be pointless in the face of activation of the same paths by drugs almost invariably applied in ischemic patients (e.g., analgesics, anesthetics, nitrovasodilators).

View larger version (13K): [in this window] [in a new window]   Fig. 2. Functional recovery of perfused mouse hearts after 60-min reperfusion after 20-min global normothermic ischemia. Shown are recoveries for left ventricular end-diastolic pressure (A) and left ventricular (LV) developed pressure (B). Hearts were divided into untreated or drug treated (AMG; 2 µM aspirin, 2 µM morphine, and 40 nM nitroglycerin applied during ischemia-reperfusion) and were either nonpreconditioned control hearts (CTRL) or subjected to ischemic Precon (IPC). Values are means ± SE (n = 6–8 per group). *P < 0.05 vs. control.

Evidence has also been presented that environmental or lifestyle factors can negatively influence conventional protective responses. For example, inhaled microparticulates affect ischemic outcomes and cardioprotection (240), and alcohol has been reported to eliminate Precon in humans (160). Such observations not only reflect the potential for inhibition of conventional responses via environmental or modifiable lifestyle factors but also highlight the possible effect of such factors on pathogenesis of ischemic heart disease (e.g., 11).

Caffeine intake is another lifestyle factor that may influence I/R tolerance and cardioprotection. A recent study by Riksen et al. (180) found that the equivalent of two to four cups of coffee effectively eliminated the benefit with two differing Precon stimuli in human tissue (in vitro and in vivo). This likely occurs via blockade of adenosine receptors, as the extracellular levels achieved act primarily (if not solely) via adenosine receptor antagonism. Animal studies reveal caffeine consumption exaggerates injury with I/R, although it appears that acute caffeine ingestion is detrimental, whereas chronic caffeine intake is without effect (possibly due to development of tolerance; Ref. 181). Epidemiological evidence indicates that more than five cups of coffee per day increases the risk for cardiovascular disease (68, 108). Moreover, retarded caffeine metabolism exaggerates this association, with only two to three cups per day associated with an increased risk of infarction (34). These linkages may well reflect inhibition of intrinsic protective mechanisms revolving around adenosine receptor engagement, including Precon and Postcon (48, 77).

Sex Dependence of Conventional Protection

In the clinical setting, assumptions of general physiological parity between males and females have led to both being evaluated and treated similarly. However, experimental and clinical findings provide evidence of fundamental disparities between the sexes that in the cardiovascular system range from coronary vessel size through to intrinsic sensitivity to ischemia. Moreover, the etiology of myocardial ischemia may differ in females vs. males (147, 191). Thus sex-dependent approaches may be required for effective treatment of ischemic heart disease. Despite evidence of sex-dependent responses and the emerging notion of sex-dependent therapy, the vast majority of research into I/R and cardioprotection continues to be performed in males (typically young and healthy). Even randomized clinical trials in acute coronary syndromes still underrepresent females (130). Our knowledge of injury processes, intrinsic protective responses, and experimental cardioprotection in the female heart is thus limited. Available evidence regarding sex differences in ischemic tolerance and protection has been well reviewed recently (154).

Conflicting data continue to be acquired regarding the sex dependence of cardioprotective responses, whereas a less equivocal case has been presented for the sex dependence of intrinsic ischemic tolerance. A majority of evidence supports greater tolerance to ischemic insult in female animal models (10, 21, 62, 168, 220, 228–230) and in humans (191). Nonetheless, sex dependence of ischemic tolerance is still debated, as a number of other studies (148, 149, 193) failed to detect differences in intrinsic sensitivity to I/R.

The mechanistic basis of sex-dependent responses to I/R and cardioprotection is under investigation, with several possible contributors. Estrogen itself is protective, contributing to ischemic tolerance in females. This involves a nuclear receptor-triggered genomic response, modulating the expression of proteins involved in protection and metabolic control (154). Nongenomic effects include activation of the protective PI3K pathway and modulation of MAPK signaling (112). Gabel et al. (62) and Wang et al. (229) provide evidence that the β-form of the estrogen receptor is specifically involved in ischemic tolerance in females vs. males. When contractility or Ca²⁺ is enhanced before ischemia, females also exhibit reduced injury vs. males, which may involve enhanced NO signaling and nitrosylation of Ca²⁺ channels to limit Ca²⁺ overload (205). Brown et al. (21) report that, in addition to greater intrinsic resistance to ischemia, females exhibit reduced sensitivity to exercise as a protective stimulus, both effects being linked to differences in sarcolemmal K_ATP channel expression. In terms of the more recently uncovered Postcon phenomenon, Penna et al. (168) report that this response is sex dependent, being less efficacious in reducing infarction in females while less effectively limiting contractile dysfunction in males. They attribute these differential effects to differences in phosphorylation/activation of the RISK elements Akt and ERK.

Available evidence thus suggests that female hearts are in a partially protected state owing to the effects of estrogen, differences in protein expression, and activation of RISK elements. Although beneficial in itself, this tolerance may limit expression of additional protection via the same paths. As suggested in the findings of Wang et al. (228), enhanced nitric oxide synthase signaling may mediate greater intrinsic tolerance in female hearts, yet it is insensitive to further activation via Precon mimetics. This raises the question of whether these pathways and molecular targets, integral to the conventional protective responses of Precon and Postcon, are the most rational candidates for clinical cardioprotection in females. Certainly, evolution of a clinically effective protectant will require specific attention to sex differences in responses to both I/R and protective stimuli.

Restoration of Conventional Protection

Although considerable evidence supports age, disease, drug, and sex dependence of Precon-based interventions (and to a lesser extent more recently discovered Postcon), there is reason to believe that some of these drawbacks might be countered by "complementary" methods. Indeed, these complementary approaches may themselves confer more benefit than the cardioprotective stimulus. Specifically, exercise and caloric restriction offer the ability to restore failed protective responses in aged hearts (3, 5, 135), while simultaneously enhancing intrinsic ischemic tolerance (194, 201). It is estimated that 80% of coronary artery disease is attributable to modifiable lifestyle/environmental factors (200), particularly activity level and calorie intake. Exercise and caloric restriction may thus not only augment efficacy of protective strategies but in themselves will substantially limit the pathogenesis and incidence of heart disease. In addition to these modifiable factors, other interventions have been linked experimentally to benefit. For example, the wine component n-tyrosol was recently reported to confer protection from ischemia by inducing survival and longevity proteins that may be considered "antiaging" for the heart (183). Similarly, manipulation of caveolins has the capacity to preserve protective signaling and prevent cellular senescence (163), while overexpression of protective GPCRs can restore protection in aged hearts (81). Thus molecular-based interventions may also have the capacity to restore protective signaling and efficacy in aged (potentially diseased) tissue.

Caloric restriction. A reduction in calorie intake, whether long (19, 196) or short term (194, 195), can significantly influence the ability of the heart to withstand injury during I/R and restore protective responses in aged tissue (4, 5, 135). The cardioprotective effects of caloric restriction may be additive with those of exercise (36). Research suggests a role for reduced oxidative damage (30), particularly to mitochondrial DNA (67, 137), in the beneficial effects of caloric restriction. In keeping with mitochondrial targeting, Broderick et al. (20) present evidence for an effect of caloric restriction on mitochondrial respiration, improving oxidative phosphorylation and energy production. Transcriptional reprogramming may contribute to these effects, with microarray interrogation revealing inhibition of age-related gene changes, together with shifts in expression of transcripts involved in protection of DNA, control of apoptosis, regulation of cytoskeletal structure and function, and fatty acid metabolism (129). Masternak et al. (146) suggested a role for modified expression of genes involved in insulin signaling, while repressed inflammation may also play a role (30). A more detailed understanding of the cellular effects of calorie restriction may pave the way to the development of effective cardioprotective strategies or of a means of enhancing conventional responses in relevant patients. Such research would also more rationally underpin dietary prescription in specific disease states or risk groups.

Exercise. The cardiovascular benefits of exercise are well established, although the underlying mechanisms remain to be elucidated. It is relevant to highlight that exercise capacity is a more powerful predictor of mortality than other established risk factors for cardiovascular disease (156), with cardiorespiratory fitness a critical determinant of mortality in older patients (204). Exercise training substantially limits cardiac injury with I/R (201), can induce Precon-like responses in human myocardium (136), and can reverse age-related abnormalities in cardioprotective responses (3, 5). Reduced activity levels may well underlie or contribute to the pathogenesis of major chronic diseases including cardiovascular diseases (29).

The molecular bases of the protective and restorative properties of exercise are not fully established, with most attention fixed on shifts in antioxidant status (201) and HSP expression (176). Several studies have identified improved expression of antioxidants in hearts from exercised animals, including elevations in glutathione (44, 133, 161), glutathione redox cycle enzyme activities (8), catalase (202), and Mn-SOD (41, 202). A number of studies (44, 134, 176) have also identified beneficial shifts in HSP expression, particularly HSP72. However, much of this work is associative in nature, with changes in antioxidant expression generally not established as causally linked to shifts in ischemic tolerance. Moreover, conflict exists in terms of the effect of exercise on antioxidant systems, with some investigators observing exercise-induced reductions in expression/activity of proteins, including glutathione S-transferase (111), glutathione, and glutathione reductase (9).

An alternate or additional mechanism involves modification of protective signaling, with some parallels with pathways involved in Precon and Postcon. Evidence has been presented that exercise-mediated protection involves PI3K and Akt (243), may require nitric oxide synthase (6), and involves GPCRs that also trigger Precon (45). The question arises then as to how and why exercise retains efficacy with age or disease whereas Precon responses involving common signal elements fail? However, exercise may not only enhance kinase signaling via conventional protective pathways but may also generate shifts in signaling (102). For example, Brown et al. (22) have shown that protection with exercise involves an increased expression and contribution from sarcolemmal K_ATP channels, in contrast to mitochondrial K_ATP involvement in conventional Precon. Other studies (213) support distinct signaling in exercise vs. Precon. Further interrogation of the exercise-dependent effects in cardiac cells may not only yield novel targets for cardioprotection and identify ways of augmenting conventional responses, but may ultimately limit the incidence and progression of heart disease and other chronic illnesses. A cogent case is presented by Chakravarthy and Booth (29) that increased caloric intake and reduced activity level in modernized societies leads to dysregulation of our Paleolithic transcriptome and a maladapted phenotype that underlies major chronic diseases.

Summary

In this brief review, we have highlighted some of the features of the most intensely studied protective phenomena (Precon and Postcon) that are highly relevant to translation and clinical utility. While research into conditioning responses continues to generate important knowledge regarding cellular injury and protection during I/R, they share features that may limit their utility and efficacy in the clinical setting. No pharmacotherapy is without drawbacks, interactions, or side effects. Nonetheless, in the search for effective cardioprotective strategies, a number of fundamental requirements should be met, most notably efficacy in the target population. In the context of ischemic heart disease, this population encompasses males and females, the majority >50 years of age, suffering comorbidities including diabetes/dyslipidemia/obesity, and often experiencing a progressive onset of disease. Each of these descriptors raises a concern regarding Precon/Postcon-based strategies: the efficacy of these responses appears to be sex dependent, the responses are negated or inhibited with aging, disease states such as diabetes additionally impair efficacy, and the underlying molecular signaling and effectors may already be activated by prior ischemia, surgical intervention, and drugs that cardiac patients might commonly be exposed to (anesthetics, analgesics, and vasodilators). Other commonly used drugs may block protection (anti-inflammatories, β-blockers, -blockers, hypoglycemic agents, and Ca²⁺ channel blockers). While one or two such complications might be manageable, more probable coexistence of several of these factors seems likely to negate the benefit from Precon/Postcon-based strategies. This does not necessarily preclude the utility of such interventions, as it is feasible to manipulate the effects of age or disease on these responses, and a more detailed understanding of the molecular processes involved in age- and disease-dependent changes in protective responses could yield other rational targets. For example, if a signaling basis to failed cardioprotection holds true, then therapy targeting more downstream components of the protective cascade (beyond sites of signal dysfunction) may prove more effective. Additionally, further information on efficacy under relevant conditions might facilitate effective application of such interventions in select responsive cohorts (e.g., pediatric patients).

Nonetheless, it is pertinent at this juncture to reexamine our rationale for studying the molecular mechanics of conditioning responses in a quest for clinical cardioprotection. Although some of the abovementioned drawbacks might be countered by complementary exercise or calorie restriction regimes, one is left considering whether these latter interventions should be a greater focus in primary prevention, rather than as post hoc manipulations to enhance the efficacy of secondary or tertiary pharmacotherapy. Either way, it is imperative that we modify our experimental approach, away from analysis of responses in young healthy males, to focus on the mechanisms and efficacy of cardioprotection in aged diseased hearts from both sexes.

GRANTS

We thank the National Heart Foundation of Australia and National Health and Medical Research Council of Australia for grant support. J. N. Peart was the recipient of fellowship support from the National Health and Medical Research Council of Australia.

FOOTNOTES

Address for reprint requests and other correspondence: J. N. Peart, Heart Foundation Research Centre, Griffith Univ., PMB 50 Gold Coast Mail Centre, QLD, 9726, Australia (e-mail: j.peart{at}griffith.edu.au)

REFERENCES

1. Abete P, Ferrara N, Cioppa A, Ferrara P, Bianco S, Calabrese C, Cacciatore F, Longobardi G, Rengo F. Preconditioning does not prevent postischemic dysfunction in aging heart. J Am Coll Cardiol 27: 1777–1786, 1996.[Abstract]
2. Abete P, Ferrara N, Cacciatore F, Madrid A, Bianco S, Calabrese C, Napoli C, Scognamiglio P, Bollella O, Cioppa A, Longobardi G, Rengo F. Angina-induced protection against myocardial infarction in adult and elderly patients: a loss of preconditioning mechanism in the aging heart? J Am Coll Cardiol 30: 947–954, 1997.[Abstract]
3. Abete P, Calabrese C, Ferrara N, Cioppa A, Pisanelli P, Cacciatore F, Longobardi G, Napoli C, Rengo F. Exercise training restores ischemic preconditioning in the aging heart. J Am Coll Cardiol 36: 643–650, 2000.[Abstract/Free Full Text]
4. Abete P, Testa G, Ferrara N, De Santis D, Capaccio P, Viati L, Calabrese C, Cacciatore F, Longobardi G, Condorelli M, Napoli C, Rengo F. Cardioprotective effect of ischemic preconditioning is preserved in food-restricted senescent rats. Am J Physiol Heart Circ Physiol 282: H1978–H1987, 2002.[Abstract/Free Full Text]
5. Abete P, Testa G, Galizia G, Mazzella F, Della Morte D, de Santis D, Calabrese C, Cacciatore F, Gargiulo G, Ferrara N, Rengo G, Sica V, Napoli C, Rengo F. Tandem action of exercise training and food restriction completely preserves ischemic preconditioning in the aging heart. Exp Gerontol 40: 43–50, 2005.[CrossRef][Web of Science][Medline]
6. Akita Y, Otani H, Matsuhisa S, Kyoi S, Enoki C, Hattori R, Imamura H, Kamihata H, Kimura Y, Iwasaka T. Exercise-induced activation of cardiac sympathetic nerve triggers cardioprotection via redox-sensitive activation of eNOS and upregulation of iNOS. Am J Physiol Heart Circ Physiol 292: H2051–H2059, 2007.[Abstract/Free Full Text]
7. Ali ZA, Callaghan CJ, Lim E, Ali AA, Nouraei SA, Akthar AM, Boyle JR, Varty K, Kharbanda RK, Dutka DP, Gaunt ME. Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial. Circulation 116: I98–I105, 2007.[CrossRef][Web of Science][Medline]
8. Atalay M, Seene T, Hänninen O, Sen CK. Skeletal muscle and heart antioxidant defences in response to sprint training. Acta Physiol Scand 158: 129–134, 1996.[CrossRef][Web of Science][Medline]
9. Aydin C, Ince E, Koparan S, Cangul IT, Naziroglu M, Ak F. Protective effects of long term dietary restriction on swimming exercise-induced oxidative stress in the liver, heart and kidney of rat. Cell Biochem Funct 25: 129–137, 2007.[CrossRef][Web of Science][Medline]
10. Bae S, Zhang L. Gender differences in cardioprotection against ischemia/reperfusion injury in adult rat hearts: focus on Akt and protein kinase C signaling. J Pharmacol Exp Ther 315: 1125–1135, 2005.[Abstract/Free Full Text]
11. Balluz L, Wen XJ, Town M, Shire JD, Qualter J, Mokdad A. Ischemic heart disease and ambient air pollution of particulate matter 2.5 in 51 counties in the US. Public Health Rep 122: 626–633, 2007.[Web of Science][Medline]
12. Bartling B, Friedrich I, Silber RE, Simm A. Ischemic preconditioning is not cardioprotective in senescent human myocardium. Ann Thorac Surg 76: 105–111, 2003.[Abstract/Free Full Text]
13. Benjamin IJ, Guo Y, Srinivasan S, Boudina S, Taylor RP, Rajasekaran NS, Gottlieb R, Wawrousek EF, Abel ED, Bolli R. CRYAB and HSPB2 deficiency alters cardiac metabolism and paradoxically confers protection against myocardial ischemia in aging mice. Am J Physiol Heart Circ Physiol 293: H3201–H3209, 2007.[Abstract/Free Full Text]
14. Besse S, Tanguy S, Boucher F, Le Page C, Rozenberg S, Riou B, Leiris J, Swynghedauw B. Cardioprotection with cariporide, a sodium-proton exchanger inhibitor, after prolonged ischemia and reperfusion in senescent rats. Exp Gerontol 39: 1307–1314, 2004.[CrossRef][Web of Science][Medline]
15. Boengler K, Buechert A, Heinen Y, Roeskes C, Hilfiker-Kleiner D, Heusch G, Schulz R. Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice. Circ Res 102: 131–135, 2007.[CrossRef][Web of Science][Medline]
16. Boengler K, Konietzka I, Buechert A, Heinen Y, Garcia-Dorado D, Heusch G, Schulz R. Loss of ischemic preconditioning's cardioprotection in aged mouse hearts is associated with reduced gap junctional and mitochondrial levels of connexin 43. Am J Physiol Heart Circ Physiol 292: H1764–H1769, 2007.[Abstract/Free Full Text]
17. Bolli R, Becker L, Gross G, Mentzer R Jr, Balshaw D, Lathrop DA; NHLBI Working Group on the Translation of Therapies for Protecting the Heart from Ischemia. Myocardial protection at a crossroads: the need for translation into clinical therapy. Circ Res 95: 125–134, 2004.[Abstract/Free Full Text]
18. Bouhidel O, Pons S, Souktani R, Zini R, Berdeaux A, Ghaleh B. Myocardial ischemic postconditioning against ischemia-reperfusion is impaired in ob/ob mice. Am J Physiol Heart Circ Physiol 295: H1580–H1586, 2008.[Abstract/Free Full Text]
19. Broderick TL, Driedzic WR, Gillis M, Jacob J, Belke T. Effects of chronic food restriction and exercise training on the recovery of cardiac function following ischemia. J Gerontol A Biol Sci Med Sci 56: B33–B37, 2001.[Abstract/Free Full Text]
20. Broderick TL, Belke T, Driedzic WR. Effects of chronic caloric restriction on mitochondrial respiration in the ischemic reperfused rat heart. Mol Cell Biochem 233: 119–125, 2002.[CrossRef][Web of Science][Medline]
21. Brown DA, Lynch JM, Armstrong CJ, Caruso NM, Ehlers LB, Johnson MS, Moore RL. Susceptibility of the heart to ischaemia-reperfusion injury and exercise-induced cardioprotection are sex-dependent in the rat. J Physiol 564: 619–630, 2005.[Abstract/Free Full Text]
22. Brown DA, Chicco AJ, Jew KN, Johnson MS, Lynch JM, Watson PA, Moore RL. Cardioprotection afforded by chronic exercise is mediated by the sarcolemmal, and not the mitochondrial, isoform of the K_ATP channel in the rat. J Physiol 569: 913–924, 2005.[Abstract/Free Full Text]
23. Burns PG, Krunkenkamp IB, Calderone CA, Kirvaitis RJ, Gaudette GR, Levitsky S. Is the preconditioning response conserved in senescent myocardium? Ann Thorac Surg 61: 925–929, 1996.[Abstract/Free Full Text]
24. Butler KL, Huang AH, Gwathmey JK. AT1-receptor blockade enhances ischemic preconditioning in hypertrophied rat myocardium. Am J Physiol Heart Circ Physiol 277: H2482–H2487, 1999.[Abstract/Free Full Text]
25. Butler KL, Huffman LC, Koch SE, Hahn HS, Gwathmey JK. STAT-3 activation is necessary for ischemic preconditioning in hypertrophied myocardium. Am J Physiol Heart Circ Physiol 291: H797–H803, 2006.[Abstract/Free Full Text]
26. Cain BS, Meldrum DR, Cleveland JC Jr, Meng X, Banerjee A, Harken AH. Clinical L-type Ca²⁺ channel blockade prevents ischemic preconditioning of human myocardium. J Mol Cell Cardiol 31: 2191–2197, 1999.[CrossRef][Web of Science][Medline]
27. Cannon CP, Gibson CM, Lambrew CT, Shoultz DA, Levy D, French WJ, Gore JM, Weaver WD, Rogers WJ, Tiefenbrunn AJ. Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 283: 2941–2947, 2000.[Abstract/Free Full Text]
28. Carr CS, Yellon DM. Ischaemic preconditioning may abolish the protection afforded by ATP-sensitive potassium channel openers in isolated human atrial muscle. Basic Res Cardiol 92: 252–260, 1997.[CrossRef][Web of Science][Medline]
29. Chakravarthy MV, Booth FW. Eating, exercise, and "thrifty" genotypes: connecting the dots toward an evolutionary understanding of modern chronic diseases. J Appl Physiol 96: 3–10, 2004.[Abstract/Free Full Text]
30. Chandrasekar B, Nelson JF, Colston JT, Freeman GL. Calorie restriction attenuates inflammatory responses to myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 280: H2094–H2102, 2001.[Abstract/Free Full Text]
31. Cheung MM, Kharbanda RK, Konstantinov IE, Shimizu M, Frndova H, Li J, Holtby HM, Cox PN, Smallhorn JF, Van Arsdell GS, Redington AN. Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol 47: 2277–2282, 2006.[Abstract/Free Full Text]
32. Clarke SJ, Khaliulin I, Das M, Parker JE, Heesom KJ, Halestrap AP. Inhibition of mitochondrial permeability transition pore opening by ischemic preconditioning is probably mediated by reduction of oxidative stress rather than mitochondrial protein phosphorylation. Circ Res 102: 1082–1090, 2008.[Abstract/Free Full Text]
33. Cleveland JCJr, Meldrum DR, Cain BS, Banerjee A, Harken AH. Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium. Two paradoxes revisited. Circulation 96: 29–32, 1997.[Abstract/Free Full Text]
34. Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H. Coffee, CYP1A2 genotype, and risk of myocardial infarction. JAMA 295: 1135–1141, 2006.[Abstract/Free Full Text]
35. Cornelussen RN, Garnier AV, Vork MM, Geurten P, Reneman RS, van der Vusse GJ, Snoeckx LH. Heat stress protects aged hypertrophied and nonhypertrophied rat hearts against ischemic damage. Am J Physiol Heart Circ Physiol 273: H1333–H1341, 1997.[Abstract/Free Full Text]
36. Crandall DL, Feirer RP, Griffith DR, Beitz DC. Relative role of caloric restriction and exercise training upon susceptibility to isoproterenol-induced myocardial infarction in male rats. Am J Clin Nutr 34: 841–847, 1981.[Abstract/Free Full Text]
37. Cremer J, Steinhoff G, Karck M, Ahnsell T, Brandt M, Teebken OE, Hollander D, Haverich A. Ischemic preconditioning prior to myocardial protection with cold blood cardioplegia in coronary surgery. Eur J Cardiothorac Surg 12: 753–738, 1997.[Abstract]
38. Cremer J, Karck M, Ahnsel T, Steinhoff G, Brandt M, Hollander D, Teebken O, Zick G, Haverich A. Ischemic preconditioning as an adjunct to crystalloid or blood cardioplegia for myocardial protection in routine coronary surgery. Thorac Cardiovasc Surg 46: 298–301, 1998.[Web of Science][Medline]
39. Csont T, Balogh G, Csonka C, Boros I, Horváth I, Vigh L, Ferdinandy P. Hyperlipidemia induced by high cholesterol diet inhibits heat shock response in rat hearts. Biochem Biophys Res Commun 290: 1535–1538, 2002.[CrossRef][Web of Science][Medline]
40. Cutler JA. Calcium-channel blockers for hypertension–uncertainty continues. N Engl J Med 338: 679–681, 1998.[Free Full Text]
41. Darling CE, Solari PB, Smith CS, Furman MI, Przyklenk K. "Postconditioning" the human heart: multiple balloon inflations during primary angioplasty may confer cardioprotection. Basic Res Cardiol 102: 274–278, 2007.[CrossRef][Web of Science][Medline]
42. Del Valle HF, Lascano EC, Negroni JA. Ischemic preconditioning protection against stunning in conscious diabetic sheep: role of glucose, insulin, sarcolemmal and mitochondrial K_ATP channels. Cardiovasc Res 55: 642–659, 2002.[Abstract/Free Full Text]
43. Del Valle HF, Lascano EC, Negroni JA, Crottogini AJ. Absence of ischemic preconditioning protection in diabetic sheep hearts: role of sarcolemmal K_ATP channel dysfunction. Mol Cell Biochem 249: 21–30, 2003.[CrossRef][Web of Science][Medline]
44. Demirel HA, Powers SK, Zergeroglu MA, Shanely RA, Hamilton K, Coombes J, Naito H. Short-term exercise improves myocardial tolerance to in vivo ischemia-reperfusion in the rat. J Appl Physiol 91: 2205–2212, 2001.[Abstract/Free Full Text]
45. Dickson EW, Hogrefe CP, Ludwig PS, Ackermann LW, Stoll LL, Denning GM. Exercise enhances myocardial ischemic tolerance via an opioid receptor-dependent mechanism. Am J Physiol Heart Circ Physiol 294: H402–H408, 2008.[Abstract/Free Full Text]
46. Dobson GP, Jones MW. Adenosine and lidocaine: a new concept in nondepolarizing surgical myocardial arrest, protection, and preservation. J Thorac Cardiovasc Surg 127: 794–805, 2004.[Abstract/Free Full Text]
47. Dow J, Bhandari A, Kloner RA. Ischemic postconditioning's benefit on reperfusion ventricular arrhythmias is maintained in the senescent heart. J Cardiovasc Pharmacol Ther 13: 141–148, 2008.[Abstract/Free Full Text]
48. Downey JM, Davis AM, Cohen MV. Signaling pathways in ischemic preconditioning. Heart Fail Rev 12: 181–188, 2007.[CrossRef][Web of Science][Medline]
49. Ebel D, Müllenheim J, Frässdorf J, Heinen A, Huhn R, Bohlen T, Ferrari J, Südkamp H, Preckel B, Schlack W, Thämer V. Effect of acute hyperglycaemia and diabetes mellitus with and without short-term insulin treatment on myocardial ischaemic late preconditioning in the rabbit heart in vivo. Pflügers Arch 446: 175–182, 2003.[CrossRef][Web of Science][Medline]
50. Ebrahim Z, Yellon DM, Baxter GF. Ischemic preconditioning is lost in aging hypertensive rat heart: independent effects of aging and longstanding hypertension. Exp Gerontol 42: 807–814, 2007.[CrossRef][Web of Science][Medline]
51. Ebrahim Z, Yellon DM, Baxter GF. Attenuated cardioprotective response to bradykinin, but not classical ischaemic preconditioning, in DOCA-salt hypertensive left ventricular hypertrophy. Pharmacol Res 55: 42–48, 2007.[CrossRef][Web of Science][Medline]
52. Ellis SG, Henschke CI, Sandor T, Wynne J, Braunwald E, Kloner RA. Time course of functional and biochemical recovery of myocardium salvaged by reperfusion. J Am Coll Cardiol 1: 1047–1055, 1983.[Web of Science][Medline]
53. Faris B, Peynet J, Wassef M, Bel A, Mouas C, Duriez M, Menasché P. Failure of preconditioning to improve postcardioplegia stunning of minimally infarcted hearts. Ann Thorac Surg 64: 1735–1741, 1997.[Abstract/Free Full Text]
54. Feng J, Fischer G, Lucchinetti E, Zhu M, Bestmann L, Jegger D, Arras M, Pasch T, Perriard JC, Schaub MC, Zaugg M. Infarct-remodeled myocardium is receptive to protection by isoflurane postconditioning: role of protein kinase B/Akt signaling. Anesthesiology 104: 1004–1014, 2006.[CrossRef][Web of Science][Medline]
55. Feng J, Lucchinetti E, Fischer G, Zhu M, Zaugg K, Schaub MC, Zaugg M. Cardiac remodelling hinders activation of cyclooxygenase-2, diminishing protection by delayed pharmacological preconditioning: role of HIF1 alpha and CREB. Cardiovasc Res 78: 98–107, 2008.[Abstract/Free Full Text]
56. Fenton RA, Dickson EW, Meyer TE, Dobson JG Jr. Aging reduces the cardioprotective effect of ischemic preconditioning in the rat heart. J Mol Cell Cardiol 32: 1371–1375, 2000.[CrossRef][Web of Science][Medline]
57. Fenton RA, Dickson EW, Dobson JG Jr. Inhibition of phosphatase activity enhances preconditioning and limits cell death in the ischemic/reperfused aged rat heart. Life Sci 77: 3375–3388, 2005.[CrossRef][Web of Science][Medline]
58. Ferdinandy P, Szilvássy Z, Horváth LI, Csont T, Csonka C, Nagy E, Szentgyörgyi R, Nagy I, Koltai M, Dux L. Loss of pacing-induced preconditioning in rat hearts: role of nitric oxide and cholesterol-enriched diet. J Mol Cell Cardiol 29: 3321–3333, 1997.[CrossRef][Web of Science][Medline]
59. Ferdinandy P, Schulz R, Baxter GF. Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning. Pharmacol Rev 59: 418–458, 2007.[Abstract/Free Full Text]
60. Feuerstein G, Liu GL, Yue TL, Cheng HY, Hieble JP, Arch JR, Ruffolo RR Jr, Ma XL. Comparison of metoprolol and carvedilol pharmacology and cardioprotection in rabbit ischemia and reperfusion model. Eur J Pharmacol 351: 341–350, 1998.[CrossRef][Web of Science][Medline]
61. Friehs I, Stamm C, Cao-Danh H, McGowan FX, del Nido PJ. Insulin-like growth factor-1 improves postischemic recovery in hypertrophied hearts. Ann Thorac Surg 72: 1650–1656, 2001.[Abstract/Free Full Text]
62. Gabel SA, Walker VR, London RE, Steenbergen C, Korach KS, Murphy E. Estrogen receptor beta mediates gender differences in ischemia/reperfusion injury. J Mol Cell Cardiol 38: 289–297, 2005.[CrossRef][Medline]
63. Garratt KN, Brady PA, Hassinger NL, Grill DE, Terzic A, Holmes DR Jr. Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after direct angioplasty for acute myocardial infarction. J Am Coll Cardiol 33: 119–124, 1999.[Abstract/Free Full Text]
64. Ghosh S, Galiñanes M. Protection of the human heart with ischemic preconditioning during cardiac surgery: role of cardiopulmonary bypass. J Thorac Cardiovasc Surg 126: 133–142, 2003.[Abstract/Free Full Text]
65. Ghosh S, Standen NB, Galiñianes M. Failure to precondition pathological human myocardium. J Am Coll Cardiol 37: 711–718, 2001.[Abstract/Free Full Text]
66. Giricz Z, Lalu MM, Csonka C, Bencsik P, Schulz R, Ferdinandy P. Hyperlipidemia attenuates the infarct size-limiting effect of ischemic preconditioning: role of matrix metalloproteinase-2 inhibition. J Pharmacol Exp Ther 316: 154–161, 2006.[Abstract/Free Full Text]
67. Gredilla R, Sanz A, Lopez-Torres M, Barja G. Caloric restriction decreases mitochondrial free radical generation at complex I and lowers oxidative damage to mitochondrial DNA in the rat heart. FASEB J 15: 1589–1591, 2001.[Free Full Text]
68. Greenland S. A meta-analysis of coffee, myocardial infarction, and coronary death. Epidemiology 4: 366–374, 1993.[Web of Science][Medline]
69. Gross ER, Hsu AK, Gross GJ. Acute aspirin treatment abolishes, whereas acute ibuprofen treatment enhances morphine-induced cardioprotection: role of 12-lipoxygenase. J Pharmacol Exp Ther 310: 185–191, 2004.[Abstract/Free Full Text]
70. Gross ER, Hsu AK, Gross GJ. Diabetes abolishes morphine-induced cardioprotection via multiple pathways upstream of glycogen synthase kinase-3β. Diabetes 56: 127–136, 2007.[Abstract/Free Full Text]
71. Gross GJ, Peart JN. K_ATP channels and myocardial preconditioning: an update. Am J Physiol Heart Circ Physiol 285: H921–H930, 2003.[Abstract/Free Full Text]
72. Günaydin B, Cakici I, Soncul H, Kalaycioglu S, Cevik C, Sancak B, Kanzik I, Karadenizli Y. Does remote organ ischaemia trigger cardiac preconditioning during coronary artery surgery? Pharmacol Res 41: 493–436, 2000.[CrossRef][Web of Science][Medline]
73. Gundewar S, Calvert JW, Elrod JW, Lefer DJ. Cytoprotective effects of N,N,N-trimethylsphingosine during ischemia- reperfusion injury are lost in the setting of obesity and diabetes. Am J Physiol Heart Circ Physiol 293: H2462–H2471, 2007.[Abstract/Free Full Text]
74. Gysembergh A, Margonari H, Loufoua J, Ovize A, André-Fouët X, Minaire Y, Ovize M. Stretch-induced protection shares a common mechanism with ischemic preconditioning in rabbit heart. Am J Physiol Heart Circ Physiol 274: H955–H964, 1998.[Abstract/Free Full Text]
75. Halestrap AP, Clarke SJ, Khaliulin I. The role of mitochondria in protection of the heart by preconditioning. Biochim Biophys Acta 1767: 1007–1031, 2007.[Medline]
76. Hassouna A, Loubani M, Matata BM, Fowler A, Standen NB, Galiñanes M. Mitochondrial dysfunction as the cause of the failure to precondition the diabetic human myocardium. Cardiovasc Res 69: 450–458, 2006.[Abstract/Free Full Text]
77. Hausenloy DJ, Yellon DM. Preconditioning and postconditioning: united at reperfusion. Pharmacol Ther 116: 173–191, 2007.[CrossRef][Web of Science][Medline]
78. Hausenloy DJ, Mwamure PK, Venugopal V, Harris J, Barnard M, Grundy E, Ashley E, Vichare S, Di Salvo C, Kolvekar S, Hayward M, Keogh B, MacAllister RJ, Yellon DM. Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet 370: 575–679, 2007.[CrossRef][Web of Science][Medline]
79. Hausenloy DJ, Yellon DM. Clinical translation of cardioprotective strategies: report and recommendations of the Hatter Institute 5th International Workshop on Cardioprotection. Basic Res Cardiol 103: 493–500, 2008.[CrossRef][Medline]
80. He Z, Crook JE, Meschia JF, Brott TG, Dickson DW, McKinney M. Aging blunts ischemic-preconditioning-induced neuroprotection following transient global ischemia in rats. Curr Neurovasc Res 2: 365–374, 2005.[CrossRef][Web of Science][Medline]
81. Headrick JP, Willems L, Ashton KJ, Holmgren K, Peart J, Matherne GP. Ischaemic tolerance in aged mouse myocardium: the role of adenosine and effects of A₁ adenosine receptor overexpression. J Physiol 549: 823–833, 2003.[Abstract/Free Full Text]
82. Heinen A, Huhn R, Smeele KM, Zuurbier CJ, Schlack W, Preckel B, Weber NC, Hollmann MW. Helium-induced preconditioning in young and old rat heart: impact of mitochondrial Ca²⁺-sensitive potassium channel activation. Anesthesiology 109: 830–836, 2008.[CrossRef][Web of Science][Medline]
83. Heusch G. Nitroglycerin and delayed preconditioning in humans: yet another new mechanism for an old drug? Circulation 103: 2876–2878, 2001.[Free Full Text]
84. Hochhauser E, Leshem D, Kaminski O, Cheporko Y, Vidne BA, Shainberg A. The protective effect of prior ischemia reperfusion adenosine A₁ or A₃ receptor activation in the normal and hypertrophied heart. Interact Cardiovasc Thorac Surg 6: 363–368, 2007.[Abstract/Free Full Text]
85. Honma Y, Tani M, Takayama M, Yamamura K, Hasegawa H. Aging abolishes the cardioprotective effect of combination heat shock and hypoxic preconditioning in reperfused rat hearts. Basic Res Cardiol 97: 489–495, 2002.[CrossRef][Web of Science][Medline]
86. Honma Y, Tani M, Yamamura K, Takayama M, Hasegawa H. Preconditioning with heat shock further improved functional recovery in young adult but not in middle-aged rat hearts. Exp Gerontol 38: 299–306, 2003.[CrossRef][Web of Science][Medline]
87. Hoole SP, Heck PM, Sharples L, Khan SN, Duehmke R, Densem CG, Clarke SC, Shapiro LM, Schofield PM, O'Sullivan M, Dutka DP. Cardiac remote ischemic preconditioning in coronary stenting (CRISP Stent) study. a prospective, randomized control trial. Circulation 119: 820–827, 2009.[Abstract/Free Full Text]
88. Hoshida S, Yamashita N, Igarashi J, Nishida M, Hori M, Kuzuya T, Tada M. A nitric oxide donor reverses myocardial injury in rabbits with acute hypercholesterolemia. J Pharmacol Exp Ther 278: 741–746, 1996.[Abstract/Free Full Text]
89. Hu CP, Peng J, Xiao L, Ye F, Deng HW, Li YJ. Effect of age on alpha-calcitonin gene-related peptide-mediated delayed cardioprotection induced by intestinal preconditioning in rats. Regul Pept 107: 137–143, 2002.[CrossRef][Web of Science][Medline]
90. Hueb W, Uchida AH, Gersh BJ, Betti RT, Lopes N, Moffa PJ, Ferreira BM, Ramires JA, Wajchenberg BL. Effect of a hypoglycemic agent on ischemic preconditioning in patients with type 2 diabetes and stable angina pectoris. Coron Artery Dis 18: 55–59, 2007.[CrossRef][Web of Science][Medline]
91. Humphreys RA, Kane KA, Parratt JR. The influence of maturation and gender on the anti-arrhythmic effect of ischaemic preconditioning in rats. Basic Res Cardiol 94: 1–8, 1999.[CrossRef][Web of Science][Medline]
92. Hunter JC, Kostyak JC, Novotny JL, Simpson AM, Korzick DH. Estrogen deficiency decreases ischemic tolerance in the aged rat heart: Roles of PKC, PKC, Akt, and GSK3β. Am J Physiol Regul Integr Comp Physiol 292: R800–R809, 2007.[Abstract/Free Full Text]
93. Iliodromitis EK, Zoga A, Vrettou A, Andreadou I, Paraskevaidis IA, Kaklamanis L, Kremastinos DT. The effectiveness of postconditioning and preconditioning on infarct size in hypercholesterolemic and normal anesthetized rabbits. Atherosclerosis 188: 356–362, 2006.[CrossRef][Web of Science][Medline]
94. Illes RW, Swoyer KD. Prospective, randomized clinical study of ischemic preconditioning as an adjunct to intermittent cold blood cardioplegia. Ann Thorac Surg 65: 748–752, 1998.[Abstract/Free Full Text]
95. IONA Study Group. Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial. Lancet 359: 1269–1275, 2002.[CrossRef][Web of Science][Medline]
96. Ishii H, Ichimiya S, Kanashiro M, Amano T, Imai K, Murohara T, Matsubara T. Impact of a single intravenous administration of nicorandil before reperfusion in patients with ST-segment-elevation myocardial infarction. Circulation 112: 1284–1288, 2005.[Abstract/Free Full Text]
97. Iwai T, Tanonaka K, Kasahara S, Inoue R, Takeo S. Protective effect of propranolol on mitochondrial function in the ischaemic heart. Br J Pharmacol 136: 472–480, 2002.[CrossRef][Web of Science][Medline]
98. Jamnicki-Abegg M, Weihrauch D, Chiari PC, Krolikowski JG, Pagel PS, Warltier DC, Kersten JR. Diabetes abolishes sildenafil-induced cGMP-dependent protein kinase-I expression and cardioprotection. J Cardiovasc Pharmacol 50: 670–676, 2007.[CrossRef][Web of Science][Medline]
99. Jancso G, Cserepes B, Gasz B, Benko L, Ferencz A, Borsiczky B, Lantos J, Dureja A, Kiss K, Szeberényi J, Roth E. Effect of acetylsalicylic acid on nuclear factor-kappaB activation and on late preconditioning against infarction in the myocardium. J Cardiovasc Pharmacol 46: 295–301, 2005.[CrossRef][Web of Science][Medline]
100. Jenkins DP, Pugsley WB, Alkhulaifi AM, Kemp M, Hooper J, Yellon DM. Ischaemic preconditioning reduces troponin T release in patients undergoing coronary artery bypass surgery. Heart 77: 314–318, 1997.[Abstract/Free Full Text]
101. Ji B, Liu M, Liu J, Wang G, Feng W, Lu F, Shengshou H. Evaluation by cardiac troponin I: the effect of ischemic preconditioning as an adjunct to intermittent blood cardioplegia on coronary artery bypass grafting. J Card Surg 22: 394–400, 2007.[CrossRef][Web of Science][Medline]
102. Ji LL, Gomez-Cabrera MC, Vina J. Exercise and hormesis: activation of cellular antioxidant signaling pathway. Ann NY Acad Sci 1067: 425–435, 2006.[CrossRef][Medline]
103. Jneid H, Chandra M, Alshaher M, Hornung CA, Tang XL, Leesar M, Bolli R. Delayed preconditioning-mimetic actions of nitroglycerin in patients undergoing exercise tolerance tests. Circulation 111: 2565–2571, 2005.[Abstract/Free Full Text]
104. Joyeux M, Faure P, Godin-Ribuot D, Halimi S, Patel A, Yellon DM, Demenge P, Ribuot C. Heat stress fails to protect myocardium of streptozotocin-induced diabetic rats against infarction. Cardiovasc Res 43: 939–946, 1999.[Abstract/Free Full Text]
105. Jung O, Jung W, Malinski T, Wiemer G, Schoelkens BA, Linz W. Ischemic preconditioning and infarct mass: the effect of hypercholesterolemia and endothelial dysfunction. Clin Exp Hypertens 22: 165–179, 2000.[CrossRef][Web of Science][Medline]
106. Katakam PV, Jordan JE, Snipes JA, Tulbert CD, Miller AW, Busija DW. Myocardial preconditioning against ischemia-reperfusion injury is abolished in Zucker obese rats with insulin resistance. Am J Physiol Regul Integr Comp Physiol 292: R920–R926, 2007.[Abstract/Free Full Text]
107. Kavianipour M, Ronquist G, Wikström G, Waldenström A. Ischaemic preconditioning alters the energy metabolism and protects the ischaemic myocardium in a stepwise fashion. Acta Physiol Scand 178: 129–137, 2003.[CrossRef][Web of Science][Medline]
108. Kawachi I, Colditz GA, Stone CB. Does coffee drinking increase the risk of coronary heart disease? Results from a meta-analysis. Br Heart J 72: 269–275, 1994.[Abstract/Free Full Text]
109. Kehl F, Krolikowski JG, Weihrauch D, Pagel PS, Warltier DC, Kersten JR. N-acetylcysteine restores isoflurane-induced preconditioning against myocardial infarction during hyperglycemia. Anesthesiology 98: 1384–1390, 2003.[CrossRef][Web of Science][Medline]
110. Kersten JR, Toller WG, Gross ER, Pagel PS, Warltier DC. Diabetes abolishes ischemic preconditioning: role of glucose, insulin, and osmolality. Am J Physiol Heart Circ Physiol 278: H1218–H1224, 2000.[Abstract/Free Full Text]
111. Khanna S, Atalay M, Laaksonen DE, Gul M, Roy S, Sen CK. Alpha-lipoic acid supplementation: tissue glutathione homeostasis at rest and after exercise. J Appl Physiol 4: 1191–1196, 1999.
112. Kim JK, Pedram A, Razandi M, Levin ER. Estrogen prevents cardiomyocyte apoptosis through inhibition of reactive oxygen species and differential regulation of p38 kinase isoforms. J Biol Chem 281: 6760–6767, 2006.[Abstract/Free Full Text]
113. Kitakaze M, Asakura M, Kim J, Shintani Y, Asanuma H, Hamasaki T, Seguchi O, Myoishi M, Minamino T, Ohara T, Nagai Y, Nanto S, Watanabe K, Fukuzawa S, Hirayama A, Nakamura N, Kimura K, Fujii K, Ishihara M, Saito Y, Tomoike H, Kitamura S; JWIND Investigators. Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials. Lancet 370: 1483–1493, 2007.[CrossRef][Web of Science][Medline]
114. Klepzig H, Kober G, Matter C, Luus H, Schneider H, Boedeker KH, Kiowski W, Amann FW, Gruber D, Harris S, Burger W. Sulfonylureas and ischaemic preconditioning; a double-blind, placebo-controlled evaluation of glimepiride and glibenclamide. Eur Heart J 20: 439–446, 1999.[Abstract/Free Full Text]
115. Kloner RA, Rezkalla SH. Cardiac protection during acute myocardial infarction: where do we stand in 2004? J Am Coll Cardiol 44: 276–286, 2004.[Abstract/Free Full Text]
116. Kloner RA, Forman MB, Gibbons RJ, Ross AM, Alexander RW, Stone GW. Impact of time to therapy and reperfusion modality on the efficacy of adenosine in acute myocardial infarction: the AMISTAD-2 trial. Eur Heart J 27: 2400–2405, 2006.[Abstract/Free Full Text]
117. Koci I, Konstaski Z, Kaminski M, Dworakowska D, Dworakowski R. Experimental hyperlipidemia prevents the protective effect of ischemic preconditioning on the contractility and responsiveness to phenylephrine of rat-isolated stunned papillary muscle. Gen Pharmacol 33: 213–219, 1999.[CrossRef][Web of Science][Medline]
118. Kolocassides KG, Seymour AM, Galinanes M, Hearse DJ. Paradoxical effect of ischemic preconditioning on ischemic contracture? NMR studies of energy metabolism and intracellular pH in the rat heart. J Mol Cell Cardiol 28: 1045–1057, 1996.[CrossRef][Web of Science][Medline]
119. Korzick DH, Kostyak JC, Hunter JC, Saupe KW. Local delivery of PKC-activating peptide mimics ischemic preconditioning in aged hearts through GSK-3β but not F1-ATPase inactivation. Am J Physiol Heart Circ Physiol 293: H2056–H2063, 2007.[Abstract/Free Full Text]
120. Kostyak JC, Hunter JC, Korzick DH. Acute PKC inhibition limits ischaemia-reperfusion injury in the aged rat heart: role of GSK-3β. Cardiovasc Res 70: 325–334, 2006.[Abstract/Free Full Text]
121. Kremastinos DT, Bofilis E, Karavolias GK, Papalois A, Kaklamanis L, Iliodromitis EK. Preconditioning limits myocardial infarct size in hypercholesterolemic rabbits. Atherosclerosis 150: 81–89, 2000.[CrossRef][Web of Science][Medline]
122. Kristiansen SB, Løfgren B, Støttrup NB, Khatir D, Nielsen-Kudsk JE, Nielsen TT, Bøtker HE, Flyvbjerg A. Ischaemic preconditioning does not protect the heart in obese and lean animal models of type 2 diabetes. Diabetologia 47: 1716–1721, 2004.[CrossRef][Web of Science][Medline]
123. Kristo G, Yoshimura Y, Keith BJ, Mentzer RM Jr, Lasley RD. Aged rat myocardium exhibits normal adenosine receptor-mediated bradycardia and coronary vasodilation but increased adenosine agonist-mediated cardioprotection. J Gerontol A Biol Sci Med Sci 60: 1399–1404, 2005.[Abstract/Free Full Text]
124. Kyriakides ZS, Psychari S, Iliodromitis EK, Kolettis TM, Sbarouni E, Kremastinos DT. Hyperlipidemia prevents the expected reduction of myocardial ischemia on repeated balloon inflations during angioplasty. Chest 121: 1211–1215, 2002.[Abstract/Free Full Text]
125. Laskey WK, Yoon S, Calzada N, Ricciardi MJ. Concordant improvements in coronary flow reserve and ST-segment resolution during percutaneous coronary intervention for acute myocardial infarction: a benefit of postconditioning. Catheter Cardiovasc Interv 72: 212–220, 2008.[CrossRef][Web of Science][Medline]
126. Lauzier B, Delemasure S, Debin R, Collin B, Sicard P, Acar N, Bretillon L, Joffre C, Bron A, Creuzot-Garcher C, Vergely C, Rochette L. Beneficial effects of myocardial postconditioning are associated with reduced oxidative stress in a senescent mouse model. Transplantation 85: 1802–1808, 2008.[CrossRef][Web of Science][Medline]
127. Lee TM, Chou TF. Impairment of myocardial protection in type 2 diabetic patients. J Clin Endocrinol Metab 88: 531–537, 2003.[Abstract/Free Full Text]
128. Lee TM, Su SF, Chou TF, Lee YT, Tsai CH. Loss of preconditioning by attenuated activation of myocardial ATP-sensitive potassium channels in elderly patients undergoing coronary angioplasty. Circulation 105: 334–340, 2002.[Abstract/Free Full Text]
129. Lee CK, Allison DB, Brand J, Weindruch R, Prolla TA. Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts. Proc Natl Acad Sci USA 99: 14988–14993, 2002.[Abstract/Free Full Text]
130. Lee PY, Alexander KP, Hammill BG, Pasquali SK, Peterson ED. Representation of elderly persons and women in published randomized trials of acute coronary syndromes. JAMA 286: 708–713, 2001.[Abstract/Free Full Text]
131. Leesar MA, Stoddard MF, Dawn B, Jasti VG, Masden R, Bolli R. Delayed preconditioning-mimetic action of nitroglycerin in patients undergoing coronary angioplasty. Circulation 103: 2935–2941, 2001.[Abstract/Free Full Text]
132. Li G, Tokuno S, Tähep Id P, Vaage J, Löwbeer C, Valen G. Preconditioning protects the severely atherosclerotic mouse heart. Ann Thorac Surg 71: 1296–1303, 2001.[Abstract/Free Full Text]
133. Liu J, Yeo HC, Overvik-Douki E, Hagen T, Doniger SJ, Chyu DW, Brooks GA, Ames BN. Chronically and acutely exercised rats: biomarkers of oxidative stress and endogenous antioxidants. J Appl Physiol 89: 21–28, 2000.[Abstract/Free Full Text]
134. Locke M, Tanguay RM, Klabunde RE, Ianuzzo CD. Enhanced postischemic myocardial recovery following exercise induction of HSP 72. Am J Physiol Heart Circ Physiol 269: H320–H325, 1995.[Abstract/Free Full Text]
135. Long P, Nguyen Q, Thurow C, Broderick TL. Caloric restriction restores the cardioprotective effect of preconditioning in the rat heart. Mech Ageing Dev 123: 1411–1413, 2002.[CrossRef][Web of Science][Medline]
136. Longobardi G, Abete P, Ferrara N, Papa A, Rosiello R, Furgi G, Calabrese C, Cacciatore F, Rengo F. "Warm-up" phenomenon in adult and elderly patients with coronary artery disease: further evidence of the loss of "ischemic preconditioning" in the aging heart. J Gerontol A Biol Sci Med Sci 55: M124–M129, 2000.[Abstract/Free Full Text]
137. López-Torres M, Gredilla R, Sanz A, Barja G. Influence of aging and long-term caloric restriction on oxygen radical generation and oxidative DNA damage in rat liver mitochondria. Free Radic Biol Med 32: 882–889, 2002.[CrossRef][Web of Science][Medline]
138. Loubani M, Ghosh S, Galiñanes M. The aging human myocardium: tolerance to ischemia and responsiveness to ischemic preconditioning. J Thorac Cardiovasc Surg 126: 143–147, 2003.[Abstract/Free Full Text]
139. Lu EX, Chen SX, Yuan MD, Hu TH, Zhou HC, Luo WJ, Li GH, Xu LM. Preconditioning improves myocardial preservation in patients undergoing open heart operations. Ann Thorac Surg 64: 1320–1324, 1997.[Abstract/Free Full Text]
140. Lu R, Hu CP, Deng HW, Li YJ. Calcitonin gene-related peptide-mediated ischemic preconditioning in the rat heart: influence of age. Regul Pept 99: 183–189, 2001.[CrossRef][Web of Science][Medline]
141. Lu R, Hu CP, Peng J, Deng HW, Li YJ. Role of calcitonin gene-related peptide in ischaemic preconditioning in diabetic rat hearts. Clin Exp Pharmacol Physiol 28: 392–396, 2001.[CrossRef][Web of Science][Medline]
142. Lucchinetti E, Jamnicki M, Fischer G, Zaugg M. Preconditioning by isoflurane retains its protection against ischemia-reperfusion injury in postinfarct remodeled rat hearts. Anesth Analg 106: 17–23, 2008.[Abstract/Free Full Text]
143. Ma X, Zhang X, Li C, Luo M. Effect of postconditioning on coronary blood flow velocity and endothelial function and LV recovery after myocardial infarction. J Interv Cardiol 19: 367–375, 2006.[CrossRef][Medline]
144. Marinovic J, Ljubkovic M, Stadnicka A, Bosnjak ZJ, Bienengraeber M. Role of sarcolemmal ATP-sensitive potassium channel in oxidative stress-induced apoptosis: mitochondrial connection. Am J Physiol Heart Circ Physiol 294: H1317–H1325, 2008.[Abstract/Free Full Text]
145. Maroko PR, Kjekshus JK, Sobel BE, Watanabe T, Covell JW, Ross J Jr, Braunwald E. Factors influencing infarct size following experimental coronary artery occlusions. Circulation 43: 67–82, 1971.[Abstract/Free Full Text]
146. Masternak MM, Al-Regaiey KA,. Del Rosario Lim MM, Jimenez-Ortega V, Panici JA, Bonkowski MS, Kopchick JJ, Wang Z, Bartke A. Caloric restriction and growth hormone receptor knockout: effects on expression of genes involved in insulin action in the heart. Exp Gerontol 41: 417–429, 2006.[CrossRef][Web of Science][Medline]
147. Matyal R. Newly appreciated pathophysiology of ischemic heart disease in women mandates changes in perioperative management: a core review. Anesth Analg 107: 37–50, 2008.[Abstract/Free Full Text]
148. McCully JD, Toyoda Y, Wakiyama H, Rousou AJ, Parker RA, Levitsky S. Age- and gender-related differences in ischemia/reperfusion injury and cardioprotection: effects of diazoxide. Ann Thorac Surg 82: 117–123, 2006.[Abstract/Free Full Text]
149. McCully JD, Rousou AJ, Parker RA, Levitsky S. Age- and gender-related differences in mitochondrial oxygen consumption and calcium with cardioplegia and diazoxide. Ann Thorac Surg 83: 1102–1109, 2007.[Abstract/Free Full Text]
150. Miki T, Miura T, Tsuchida A, Nakano A, Hasegawa T, Fukuma T, Shimamoto K. Cardioprotective mechanism of ischemic preconditioning is impaired by postinfarct ventricular remodeling through angiotensin II type 1 receptor activation. Circulation 102: 458–463, 2000.[Abstract/Free Full Text]
151. Mio Y, Bienengraeber MW, Marinovic J, Gutterman DD, Rakic M, Bosnjak ZJ, Stadnicka A. Age-related attenuation of isoflurane preconditioning in human atrial cardiomyocytes: roles for mitochondrial respiration and sarcolemmal adenosine triphosphate-sensitive potassium channel activity. Anesthesiology 108: 612–620, 2008.[Web of Science][Medline]
152. Miura T, Miki T. Limitation of myocardial infarct size in the clinical setting: current status and challenges in translating animal experiments into clinical therapy. Basic Res Cardiol 103: 501–513, 2008.[CrossRef][Web of Science][Medline]
153. Moolman JA, Genade S, Tromp E, Opie LH, Lochner A. Ischaemic preconditioning does not protect hypertrophied myocardium against ischaemia. S Afr Med J 87, Suppl 3: C151–C156, 1997.[Web of Science][Medline]
154. Murphy E, Steenbergen C. Gender-based differences in mechanisms of protection in myocardial ischemia-reperfusion injury. Cardiovasc Res 75: 478–486, 2007.[Abstract/Free Full Text]
155. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74: 1124–1136, 1986.[Abstract/Free Full Text]
156. Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med 346: 793–801, 2000.[CrossRef]
157. Nakagawa C, Asayama J, Katamura M, Matoba S, Keira N, Kawahara A, Tsuruyama K, Tanaka T, Kobara M, Akashi K, Ohta B, Tatsumi T, Nakagawa M. Myocardial stretch induced by increased left ventricular diastolic pressure preconditions isolated perfused hearts of normotensive and spontaneously hypertensive rats. Basic Res Cardiol 92: 410–416, 1997.[Web of Science][Medline]
158. Nakai Y, Horimoto H, Mieno S, Sasaki S. Na⁺/H⁺ exchanger inhibitor HOE642 offers myoprotection in senescent myocardium independent of ischemic preconditioning mechanisms. Eur Surg Res 34: 244–250, 2002.[CrossRef][Web of Science][Medline]
159. Napoli C, Liguori A, Cacciatore F, Rengo F, Ambrosio G, Abete P. "Warm-up" phenomenon detected by electrocardiographic ambulatory monitoring in adult and older patients. J Am Geriatr Soc 47: 1114–1117, 1999.[Web of Science][Medline]
160. Niccoli G, Altamura L, Fabretti A, Lanza GA, Biasucci LM, Rebuzzi AG, Leone AM, Porto I, Burzotta F, Trani C, Crea F. Ethanol abolishes ischemic preconditioning in humans. J Am Coll Cardiol 51: 271–275, 2008.[Abstract/Free Full Text]
161. Ohkuwa T, Sato Y, Naoi M. Glutathione status and reactive oxygen generation in tissues of young and old exercised rats. Acta Physiol Scand 3: 237–244, 1997.
162. Pantos CI, Davos CH, Carageorgiou HC, Varonos DV, Cokkinos DV. Ischaemic preconditioning protects against myocardial dysfunction caused by ischaemia in isolated hypertrophied rat hearts. Basic Res Cardiol 91: 444–449, 1996.[CrossRef][Web of Science][Medline]
163. Park SC. New molecular target for modulation of aging process. Antioxid Redox Signal 8: 620–627, 2006.[CrossRef][Web of Science][Medline]
164. Peart JN, Gross GJ. Chronic exposure to morphine produces a marked cardioprotective phenotype in aged mouse hearts. Exp Gerontol 39: 1021–1026, 2004.[CrossRef][Web of Science][Medline]
165. Peart JN, Gross ER, Headrick JP, Gross GJ. Impaired p38 MAPK/HSP27 signaling underlies aging-related failure in opioid-mediated cardioprotection. J Mol Cell Cardiol 42: 972–980, 2007.[CrossRef][Web of Science][Medline]
166. Peart J, Willems L, Headrick JP. Receptor and non-receptor-dependent mechanisms of cardioprotection with adenosine. Am J Physiol Heart Circ Physiol 284: H519–H527, 2003.[Abstract/Free Full Text]
167. Pêgo-Fernandes PM, Jatene FB, Kwasnicka K, Hueb AC, Moreira LF, Gentil AF, Stolf NA, Oliveira SA. Ischemic preconditioning in myocardial revascularization with intermittent aortic cross-clamping. J Card Surg 15: 333–338, 2000.[CrossRef][Web of Science][Medline]
168. Penna C, Tullio F, Merlino A, Moro F, Raimondo S, Rastaldo R, Perrelli MG, Mancardi D, Pagliaro P. Postconditioning cardioprotection against infarct size and post-ischemic systolic dysfunction is influenced by gender. Basic Res Cardiol. 2008 Nov 22. [Epub ahead of print]
169. Penson PE, Ford WR, Kidd EJ, Broadley KJ. Activation of beta-adrenoceptors mimics preconditioning of rat-isolated atria and ventricles against ischaemic contractile dysfunction. Naunyn Schmiedebergs Arch Pharmacol 378: 589–597, 2008.[CrossRef][Web of Science][Medline]
170. Perrault LP, Menasché P, Bel A, de Chaumaray T, Peynet J, Mondry A, Olivero P, Emanoil-Ravier R, Moalic JM. Ischemic preconditioning in cardiac surgery: a word of caution. J Thorac Cardiovasc Surg 112: 1378–1386, 1996.[Abstract/Free Full Text]
171. Philipp S, Yang XM, Cui L, Davis AM, Downey JM, Cohen MV. Postconditioning protects rabbit hearts through a protein kinase C-adenosine A_2b receptor cascade. Cardiovasc Res 70: 308–314, 2006.[Abstract/Free Full Text]
172. Przyklenk K, Li G, Simkhovich BZ, Kloner RA. Mechanisms of myocardial ischemic preconditioning are age related: PKC- does not play a requisite role in old rabbits. J Appl Physiol 95: 2563–2569, 2003.[Abstract/Free Full Text]
173. Przyklenk K, Whittaker P. In vitro platelet responsiveness to adenosine-mediated "preconditioning" is age-dependent. J Thromb Thrombolysis 19: 5–10, 2005.[CrossRef][Web of Science][Medline]
174. Przyklenk K, Maynard M, Darling CE, Whittaker P. Aging mouse hearts are refractory to infarct size reduction with post-conditioning. J Am Coll Cardiol 51: 1393–1398, 2008.[Abstract/Free Full Text]
175. Qi JS, Kam KW, Chen M, Wu S, Wong TM. Failure to confer cardioprotection and to increase the expression of heat-shock protein 70 by preconditioning with a -opioid receptor agonist during ischaemia and reperfusion in streptozotocin-induced diabetic rats. Diabetologia 47: 214–220, 2004.[CrossRef][Web of Science][Medline]
176. Quindry JC, Hamilton KL, French JP, Lee Y, Murlasits Z, Tumer N, Powers SK. Exercise-induced HSP-72 elevation and cardioprotection against infarct and apoptosis. J Appl Physiol 103: 1056–1062, 2007.[Abstract/Free Full Text]
177. Quinlan CL, Costa AD, Costa CL, Pierre SV, Dos Santos P, Garlid KD. Conditioning the heart induces formation of signalosomes that interact with mitochondria to open mitoK_ATP channels. Am J Physiol Heart Circ Physiol 295: H953–H961, 2008.[Abstract/Free Full Text]
178. Randall MD, Gardiner SM, Bennett T. Enhanced cardiac preconditioning in the isolated heart of the transgenic [(mREN-2)27] hypertensive rat. Cardiovasc Res 33: 400–409, 1997.[Abstract/Free Full Text]
179. Riess ML, Camara AK, Rhodes SS, McCormick J, Jiang MT, Stowe DF. Increasing heart size and age attenuate anesthetic preconditioning in guinea pig isolated hearts. Anesth Analg 101: 1572–1576, 2005.[Abstract/Free Full Text]
180. Riksen NP, Zhou Z, Oyen WJ, Jaspers R, Ramakers BP, Brouwer RM, Boerman OC, Steinmetz N, Smits P, Rongen GA. Caffeine prevents protection in two human models of ischemic preconditioning. J Am Coll Cardiol 48: 700–707, 2006.[Abstract/Free Full Text]
181. Rose'Meyer RB, Headrick JP, Peart JN, Harrison GJ, Garnham BG, Willis RJ. Acute but not chronic caffeine impairs functional responses to ischaemia-reperfusion in rat isolated perfused heart. Clin Exp Pharmacol Physiol 28: 19–24, 2001.[CrossRef][Web of Science][Medline]
182. Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW; AMISTADII Investigators. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II). J Am Coll Cardiol 45: 1775–1780, 2005.[Abstract/Free Full Text]
183. Samuel SM, Thirunavukkarasu M, Penumathsa SV, Paul D, Maulik N. Akt/FOXO3a/ SIRT1-mediated cardioprotection by n-tyrosol against ischemic stress in rat in vivo model of myocardial infarction: switching gears toward survival and longevity. J Agric Food Chem 56: 9692–9698, 2008.[CrossRef][Web of Science][Medline]
184. Schaller BJ. Influence of age on stroke and preconditioning-induced ischemic tolerance in the brain. Exp Neurol 205: 9–19, 2007.[CrossRef][Web of Science][Medline]
185. Schiesser M, Wittert A, Nieuwenhuijs VB, Morphett A, Padbury RT, Barritt GJ. Intermittent ischemia but not ischemic preconditioning is effective in restoring bile flow after ischemia reperfusion injury in the livers of aged rats. J Surg Res 2008 Feb 1. [Epub ahead of print]
186. Schulman D, Latchman DS, Yellon DM. Effect of aging on the ability of preconditioning to protect rat hearts from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 281: H1630–H1636, 2001.[Abstract/Free Full Text]
187. Schulz R, Post H, Vahlhaus C, Heusch G. Ischemic preconditioning in pigs: a graded phenomenon: its relation to adenosine and bradykinin. Circulation 98: 1022–1029, 1998.[Abstract/Free Full Text]
188. Schulz R, Boengler K, Totzeck A, Luo Y, Garcia-Dorado D, Heusch G. Connexin 43 in ischemic pre- and postconditioning. Heart Fail Rev 12: 261–266, 2007.[CrossRef][Web of Science][Medline]
189. Scognamiglio R, Avogaro A, Vigili de Kreutzenberg S, Negut C, Palisi M, Bagolin E, Tiengo A. Effects of treatment with sulfonylurea drugs or insulin on ischemia-induced myocardial dysfunction in type 2 diabetes. Diabetes 51: 808–812, 2002.[Abstract/Free Full Text]
190. Selzner M, Selzner N, Jochum W, Graf R, Clavien PA. Increased ischemic injury in old mouse liver: an ATP-dependent mechanism. Liver Transpl 13: 382–390, 2007.[CrossRef][Web of Science][Medline]
191. Shaw LJ, Bairey Merz CN, Pepine CJ, Reis SE, Bittner V, Kelsey SF, Olson M, Johnson BD, Mankad S, Sharaf BL, Rogers WJ, Wessel TR, Arant CB, Pohost GM, Lerman A, Quyyumi AA, Sopko G; WISE Investigators. Insights from the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study: Part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies. J Am Coll Cardiol 47, Suppl 3: S4–S20, 2006.[Abstract/Free Full Text]
192. Shinmura K, Kodani E, Xuan YT, Dawn B, Tang XL, Bolli R. Effect of aspirin on late preconditioning against myocardial stunning in conscious rabbits. J Am Coll Cardiol 41: 1183–1194, 2003.[Abstract/Free Full Text]
193. Shinmura K, Nagai M, Tamaki K, Bolli R. Gender and aging do not impair opioid-induced late preconditioning in rats. Basic Res Cardiol 99: 46–55, 2004.[CrossRef][Web of Science][Medline]
194. Shinmura K, Tamaki K, Bolli R. Short-term caloric restriction improves ischemic tolerance independent of opening of ATP-sensitive K⁺ channels in both young and aged hearts. J Mol Cell Cardiol 39: 285–296, 2005.[CrossRef][Web of Science][Medline]
195. Shinmura K, Tamaki K, Saito K, Nakano Y, Tobe T, Bolli R. Cardioprotective effects of short-term caloric restriction are mediated by adiponectin via activation of AMP-activated protein kinase. Circulation 116: 2809–2817, 2007.[Abstract/Free Full Text]
196. Shinmura K, Tamaki K, Bolli R. Impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxide-dependent increase in nuclear Sirt1. Am J Physiol Heart Circ Physiol 295: H2348–H2355, 2008.[Abstract/Free Full Text]
197. Sniecinski R, Liu H. Reduced efficacy of volatile anesthetic preconditioning with advanced age in isolated rat myocardium. Anesthesiology 100: 589–597, 2004.[CrossRef][Web of Science][Medline]
198. Speechly-Dick ME, Baxter GF, Yellon DM. Ischaemic preconditioning protects hypertrophied myocardium. Cardiovasc Res 28: 1025–1029, 1994.[Abstract/Free Full Text]
199. Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I, Aupetit JF, Bonnefoy E, Finet G, André-Fouët X, Ovize M. Postconditioning the human heart. Circulation 112: 2143–2148, 2005.[Abstract/Free Full Text]
200. Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med 343: 16–22, 2000.[Abstract/Free Full Text]
201. Starnes JW, Taylor RP. Exercise-induced cardioprotection: endogenous mechanisms. Med Sci Sports Exerc 39: 1537–1543, 2007.[CrossRef][Web of Science][Medline]
202. Starnes JW, Taylor RP, Park Y. Exercise improves postischemic function in aging hearts. Am J Physiol Heart Circ Physiol 285: H347–H351, 2003.[Abstract/Free Full Text]
203. Suematsu Y, Anttila V, Takamoto S, del Nido P. Cardioprotection afforded by ischemic preconditioning interferes with chronic beta-blocker treatment. Scand Cardiovasc J 38: 293–299, 2004.[CrossRef][Web of Science][Medline]
204. Sui X, LaMonte MJ, Laditka JN, Hardin JW, Chase N, Hooker SP, Blair SN. Cardiorespiratory fitness and adiposity as mortality predictors in older adults. JAMA 298: 2507–2516, 2007.[Abstract/Free Full Text]
205. Sun J, Picht E, Ginsburg KS, Bers DM, Steenbergen C, Murphy E. Hypercontractile female hearts exhibit increased S-nitrosylation of the L-type Ca²⁺ channel 1 subunit and reduced ischemia/reperfusion injury. Circ Res 98: 403–411, 2006.[Abstract/Free Full Text]
206. Szilvássy Z, Ferdinandy P, Szilvássy J, Nagy I, Karcsu S, Lonovics J, Dux L, Koltai M. The loss of pacing-induced preconditioning in atherosclerotic rabbits: role of hypercholesterolaemia. J Mol Cell Cardiol 27: 2559–2569, 1995.[CrossRef][Web of Science][Medline]
207. Szmagala P, Morawski W, Krejca M, Gburek T, Bochenek A. Evaluation of perioperative myocardial tissue damage in ischemically preconditioned human heart during aorto coronary bypass surgery. J Cardiovasc Surg (Torino) 39: 791–795, 1998.[Medline]
208. Takayama M, Ebihara Y, Tani M. Differences in the expression of protein kinase C isoforms and its translocation after stimulation with phorbol ester between young-adult and middle-aged ventricular cardiomyocytes isolated from Fischer 344 rats. Jpn Circ J 65: 1071–1076, 2001.[CrossRef][Medline]
209. Tanaka K, Kehl F, Gu W, Krolikowski JG, Pagel PS, Warltier DC, Kersten JR. Isoflurane-induced preconditioning is attenuated by diabetes. Am J Physiol Heart Circ Physiol 282: H2018–H2023, 2002.[Abstract/Free Full Text]
210. Tani M, Suganuma Y, Hasegawa H, Shinmura K, Hayashi Y, Guo X, Nakamura Y. Changes in ischemic tolerance and effects of ischemic preconditioning in middle-aged rat hearts. Circulation 95: 2559–2566, 1997.[Abstract/Free Full Text]
211. Tani M, Honma Y, Takayama M, Hasegawa H, Shinmura K, Ebihara Y, Tamaki K. Loss of protection by hypoxic preconditioning in aging Fischer 344 rat hearts related to myocardial glycogen content and Na⁺ imbalance. Cardiovasc Res 41: 594–602, 1999.[Abstract/Free Full Text]
212. Tani M, Honma Y, Hasegawa H, Tamaki K. Direct activation of mitochondrial K_ATP channels mimics preconditioning but protein kinase C activation is less effective in middle-aged rat hearts. Cardiovasc Res 49: 56–68, 2001.[Abstract/Free Full Text]
213. Taylor RP, Olsen ME, Starnes JW. Improved postischemic function following acute exercise is not mediated by nitric oxide synthase in the rat heart. Am J Physiol Heart Circ Physiol 292: H601–H607, 2007.[Abstract/Free Full Text]
214. Teoh LK, Grant R, Hulf JA, Pugsley WB, Yellon DM. The effect of preconditioning [ischemic and pharmacological] on myocardial necrosis following coronary artery bypass graft surgery. Cardiovasc Res 53: 175–180, 2002.[Abstract/Free Full Text]
215. Teoh LK, Grant R, Hulf JA, Pugsley WB, Yellon DM. A comparison between ischemic preconditioning, intermittent cross-clamp fibrillation and cold crystalloid cardioplegia for myocardial protection during coronary artery bypass graft surgery. Cardiovasc Surg 10: 251–255, 2002.[CrossRef][Web of Science][Medline]
216. Thibault H, Piot C, Staat P, Bontemps L, Sportouch C, Rioufol G, Cung TT, Bonnefoy E, Angoulvant D, Aupetit JF, Finet G, André-Fouët X, Macia JC, Raczka F, Rossi R, Itti R, Kirkorian G, Derumeaux G, Ovize M. Long-term benefit of postconditioning. Circulation 117: 1037–1044, 2008.[Abstract/Free Full Text]
217. Tomai F, Crea F, Gaspardone A, Versaci F, Ghini AS, De Paulis R, Chiariello L, Gioffrè PA. Phentolamine prevents adaptation to ischemia during coronary angioplasty: role of -adrenergic receptors in ischemic preconditioning. Circulation 96: 2171–2177, 1997.[Abstract/Free Full Text]
218. Tosaki A, Engelman DT, Engelman RM, Das DK. The evolution of diabetic response to ischemia/reperfusion and preconditioning in isolated working rat hearts. Cardiovasc Res 31: 526–536, 1996.[Abstract/Free Full Text]
219. Tsang A, Hausenloy DJ, Mocanu MM, Carr RD, Yellon DM. Preconditioning the diabetic heart: the importance of Akt phosphorylation. Diabetes 54: 2360–2364, 2005.[Abstract/Free Full Text]
220. Turcato S, Turnbull L, Wang GY, Honbo N, Simpson PC, Karliner JS, Baker AJ. Ischemic preconditioning depends on age and gender. Basic Res Cardiol 101: 235–243, 2006.[CrossRef][Web of Science][Medline]
221. Ueda Y, Kitakaze M, Komamura K, Minamino T, Asanuma H, Sato H, Kuzuya T, Takeda H, Hori M. Pravastatin restored the infarct size-limiting effect of ischemic preconditioning blunted by hypercholesterolemia in the rabbit model of myocardial infarction. J Am Coll Cardiol 34: 2120–2125, 1999.[Abstract/Free Full Text]
222. Ungi I, Ungi T, Ruzsa Z, Nagy E, Zimmermann Z, Csont T, Ferdinandy P. Hypercholesterolemia attenuates the anti-ischemic effect of preconditioning during coronary angioplasty. Chest 128: 1623–1628, 2005.[Abstract/Free Full Text]
223. Vigh L, Maresca B, Harwood JL. Does the membrane's physical state control the expression of heat shock and other genes? Trends Biochem Sci 23: 369–374, 1998.[CrossRef][Web of Science][Medline]
224. Wagner C, Kloeting I, Strasser RH, Weinbrenner C. Cardioprotection by postconditioning is lost in WOKW rats with metabolic syndrome: role of glycogen synthase kinase 3beta. J Cardiovasc Pharmacol 52: 430–437, 2008.[CrossRef][Web of Science][Medline]
225. Walker DM, Walker JM, Pugsley WB, Pattison CW, Yellon DM. Preconditioning in isolated superfused human muscle. J Mol Cell Cardiol 27: 1349–1357, 1995.[CrossRef][Web of Science][Medline]
226. Wan TC, Ge ZD, Tampo A, Mio Y, Bienengraeber MW, Tracey WR, Gross GJ, Kwok WM, Auchampach JA. The A₃ adenosine receptor agonist CP-532,903 [N⁶-(2,5-dichlorobenzyl)-3'-aminoadenosine-5'-N-methylcarboxamide] protects against myocardial ischemia/reperfusion injury via the sarcolemmal ATP-sensitive potassium channel. J Pharmacol Exp Ther 324: 234–243, 2008.[Abstract/Free Full Text]
227. Wang TD, Chen WJ, Mau TJ, Lin JW, Lin WW, Lee YT. Attenuation of increased myocardial ischaemia-reperfusion injury conferred by hypercholesterolaemia through pharmacological inhibition of the caspase-1 cascade. Br J Pharmacol 138: 291–300, 2003.[CrossRef][Web of Science][Medline]
228. Wang C, Chiari PC, Weihrauch D, Krolikowski JG, Warltier DC, Kersten JR, Pratt PF Jr, Pagel PS. Gender-specificity of delayed preconditioning by isoflurane in rabbits: potential role of endothelial nitric oxide synthase. Anesth Analg 103: 274–280, 2006.[Abstract/Free Full Text]
229. Wang M, Crisostomo PR, Markel T, Wang Y, Lillemoe KD, Meldrum DR. Estrogen receptor beta mediates acute myocardial protection following ischemia. Surgery 144: 233–238, 2008.[CrossRef][Web of Science][Medline]
230. Willems L, Zatta A, Holmgren K, Ashton KJ, Headrick JP. Age-related changes in ischemic tolerance in male and female mouse hearts. J Mol Cell Cardiol 38: 245–256, 2005.[CrossRef][Medline]
231. Willems L, Ashton KJ, Headrick JP. Adenosine-mediated cardioprotection in the aging myocardium. Cardiovasc Res 66: 245–255, 2005.[Abstract/Free Full Text]
232. Williams SC, Schmaltz SP, Morton DJ, Koss RG, Loeb JM. Quality of care in US hospitals as reflected by standardized measures, 2002–2004. N Engl J Med 353: 255–264, 2005.[Abstract/Free Full Text]
233. Wu ZK, Tarkka MR, Pehkonen E, Kaukinen L, Honkonen EL, Kaukinen S. Ischaemic preconditioning has a beneficial effect on left ventricular haemodynamic function after a coronary artery biopass grafting operation. Scand Cardiovasc J 34: 247–253, 2000.[Web of Science][Medline]
234. Wu ZK, Pehkonen E, Laurikka J, Kaukinen L, Honkonen EL, Kaukinen S, Tarkka MR. Ischemic preconditioning protects right ventricular function in coronary artery bypass grafting patients experiencing angina within 48–72 hours. J Cardiovasc Surg (Torino) 43: 319–326, 2002.[Medline]
235. Wu ZK, Tarkka MR, Eloranta J, Pehkonen E, Laurikka J, Kaukinen L, Honkonen EL, Vuolle M, Kaukinen S. Effect of ischaemic preconditioning, cardiopulmonary bypass and myocardial ischaemic/reperfusion on free radical generation in CABG patients. Cardiovasc Surg 9: 362–368, 2001.[CrossRef][Web of Science][Medline]
236. Wu ZK, Iivainen T, Pehkonen E, Laurikka J, Tarkka MR. Ischemic preconditioning suppresses ventricular tachyarrhythmias after myocardial revascularization. Circulation 106: 3091–3096, 2002.[Abstract/Free Full Text]
237. Yang XC, Liu Y, Wang LF, Cui L, Wang T, Ge YG, Wang HS, Li WM, Xu L, Ni ZH, Liu SH, Zhang L, Jia HM, Vinten-Johansen J, Zhao ZQ. Reduction in myocardial infarct size by postconditioning in patients after percutaneous coronary intervention. J Invasive Cardiol 19: 424–430, 2007.[Medline]
238. Yellon DM, Alkhulaifi AM, Pugsley WB. Preconditioning the human myocardium. Lancet 342: 276–277, 1993.[CrossRef][Web of Science][Medline]
239. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 357: 1121–1135, 2007.[Free Full Text]
240. Yokota S, Furuya M, Seki T, Marumo H, Ohara N, Kato A. Delayed exacerbation of acute myocardial ischemia/reperfusion-induced arrhythmia by tracheal instillation of diesel exhaust particles. Inhal Toxicol 16: 319–331, 2004.[CrossRef][Web of Science][Medline]
241. Yvon A, Hanouz JL, Haelewyn B, Terrien X, Massetti M, Babatasi G, Khayat A, Ducouret P, Bricard H, Gérard JL. Mechanisms of sevoflurane-induced myocardial preconditioning in isolated human right atria in vitro. Anesthesiology 99: 27–33, 2003.[CrossRef][Web of Science][Medline]
242. Zaman MB, Leonard MO, Ryan EJ, Nolan NP, Hoti E, Maguire D, Mulcahy H, Traynor O, Taylor CT, Hegarty JE, Geoghegan JG, O'Farrelly C. Lower expression of Nrf2 mRNA in older donor livers: a possible contributor to increased ischemia-reperfusion injury? Transplantation 84: 1272–1278, 2007.[CrossRef][Web of Science][Medline]
243. Zhang KR, Liu HT, Zhang HF, Zhang QJ, Li QX, Yu QJ, Guo WY, Wang HC, Gao F. Long-term aerobic exercise protects the heart against ischemia/reperfusion injury via PI3 kinase-dependent and Akt-mediated mechanism. Apoptosis 12: 1579–1588, 2007.[CrossRef][Web of Science][Medline]
244. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285: H579–H588, 2003.[Abstract/Free Full Text]

This article has been cited by other articles:

				G. Heusch and R. Schulz Neglect of the coronary circulation: some critical remarks on problems in the translation of cardioprotection Cardiovasc Res, October 1, 2009; 84(1): 11 - 14. [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 296/6/H1705    most recent 00162.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Peart, J. N. Articles by Headrick, J. P. Search for Related Content PubMed PubMed Citation Articles by Peart, J. N. Articles by Headrick, J. P.