(Circulation. 1999;100:559-563.)
© 1999 American Heart Association, Inc.
Current Perspective |
Ischemic Preconditioning in Humans
Models, Mediators, and Clinical Relevance
From the Divisione di Cardiochirurgia, Università di Roma Tor Vergata, European Hospital and Istituto di Cardiologia (F.C.), Università Cattolica del Sacro Cuore, Rome, Italy.
Correspondence to Dr Fabrizio Tomai, Divisione di Cardiochirurgia, Università di Roma Tor Vergata, European Hospital, via Portuense 700, 00149 Rome, Italy.
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Abstract |
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Abstract—Ischemic preconditioning, a powerful form of endogenous protection against myocardial infarction, has been demonstrated in several animal species and, recently, in isolated human cardiomyocytes. For both logistic and ethical reasons, no clinical study can meet the strict conditions of experimental studies on preconditioning with infarct size as the end-point. Nevertheless, the demonstration of adaptation to ischemia observed during in vitro studies on human atrial trabeculae, in patients in the setting of coronary bypass surgery, and in the setting of coronary angioplasty in the absence of collateral vessel recruitment strongly suggests that ischemic preconditioning occurs in humans. This notion is further supported by the observation that in these human models, the adaptation to ischemia is influenced by drugs acting on KATP channels and on purinergic and
-adrenergic receptors, similar to what is observed in accepted
experimental models of ischemic preconditioning. This important
form of myocardial endogenous protection may also play a
role in the warm-up phenomenon and in mediating the beneficial effects
of preinfarction angina. The demonstration of ischemic
preconditioning in humans and the identification of some of its
mediators suggests that in patients at high risk for myocardial
infarction, drugs known to block this endogenous form of
protection should be used with caution, whereas drugs known to elicit
preconditioning might have a relevant therapeutic role.
Key Words: angina • ischemia • myocardial infarction
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Introduction |
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Ischemic preconditioning refers to the ability of short periods of ischemia to make the myocardium more resistant to a subsequent ischemic insult. This term was introduced for the first time by Murry et al, who found in a canine model that 4 consecutive periods of coronary occlusion of 5 minutes were able to reduce the infarct size caused by a subsequent period of occlusion of 40 minutes by as much as 75%.1 This classic form of ischemic preconditioning has now been observed in several animal species.
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Ischemic Preconditioning: Definition and Experimental Models |
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Although ischemic preconditioning initially referred to the ability of short periods of ischemia to limit infarct size,1 some investigators extended this definition to include a beneficial effect on ischemia- and reperfusion-induced arrhythmias2 and on myocardial stunning.3 It is questionable, however, whether the reduction in the incidence of arrhythmias by ischemic preconditioning is a result of a direct antiarrhythmic effect or a mere consequence of the delay of ischemic cell death.1 2 Regarding the beneficial effects of ischemic preconditioning on postischemic contractile dysfunction, Cohen et al3 showed that preconditioning in rabbits can lead to enhanced recovery of contractile function of the myocardial region at risk. Also, in this case, the beneficial effects of preconditioning on acute recovery of contractile function might be a consequence of the delay of ischemic cell death; indeed, parameters of necrosis extent, ie, infarct size and enzyme leakage, correlate with the enhancement of functional recovery.3
The chain of events which confers resistance to ischemia is only partially understood. Recently, Downey and coworkers have developed the hypothesis that stimulation of a variety of G protein-coupled receptors results in the activation of protein kinase C (PKC). This, in turn, leads to the translocation of PKC from the cytoplasm to the sarcolemma, where it phosphorylates a substrate protein (possibly the ATP-sensitive K+[KATP] channel), which confers resistance to ischemia.4
It is now well established that the protective effects of preconditioning are transient and last for <2 hours.4 However, a so-called second window of protection or delayed ischemic preconditioning has been shown in different species, occurring 24 hours after the preconditioning stimulus and lasting for about 48 hours.5 This time course is consistent with the concept that the second window of protection is mediated by the activation of genes encoding for cytoprotective proteins, such as heat shock proteins or antioxidant enzymes.5 Similar to the early phase of preconditioning, aside from a delayed anti-infarct effect, a delayed anti-arrhythmic effect following preconditioning has been reported.6 Furthermore, Bolli's group7 has recently described a delayed preconditioning against myocardial stunning, independent of ischemic necrosis because the ischemic challenge used was insufficient to induce infarction.
Ischemic Preconditioning in Humans
Experimental findings on ischemic preconditioning cannot
be directly extrapolated to humans because its mechanisms are different
from other animal species. Unfortunately, for both logistic and ethical
reasons, no clinical study can meet the strict conditions of
experimental studies on preconditioning in which infarct size is the
end-point. Thus, surrogate end-points have been used, including
contractile function, electrocardiographic ischemic changes, or
biochemical evidence of cell damage. These have to be taken into
account in the evaluation of clinical studies on preconditioning, as
the mechanisms of such nonclassic forms of ischemic
preconditioning may differ from those involved in the reduction of
infarct size in the experimental models. Another important limitation
of several clinical studies reported is represented by the
extent of coronary collateral flow, which, in humans, is a
major determinant of the severity of myocardial ischemia during
coronary occlusion; it cannot always be accurately
quantified.
In Vitro Human Studies
In vitro human studies, in which confounding effects due to
coronary collateral flow can be overcome, have shown that human
cardiomyocytes can be preconditioned.8 9 10 11
Yellon and his coworkers8 showed that isolated,
superfused, isometrically contracting human atrial
trabeculae can be preconditioned against a combined hypoxic
and substrate depletion challenge by simulated ischemia and by
A1 and A3 adenosine
receptor activation. The same group has also demonstrated that
protection against contractile dysfunction caused by a combined hypoxic
and substrate depletion challenge can be induced by activation of PKC
and by the opening of KATP channels, and the
protection induced by PKC activation and preconditioning can be blocked
by blockade of KATP channels.9
Very recently, Cleveland et al10 have shown that in this model protection is not evident when the myocardium is obtained from diabetic patients exposed to long-term oral hypoglycemic agents, thus suggesting important clinical implications. Finally, Morris and Yellon11 have shown in human atrial trabeculae that angiotensin-converting enzyme inhibitors can potentiate the protective effects of a subthreshold preconditioning stimulus, possibly because of bradykinin degradation inhibition resulting in enhanced B2-bradykinin receptor activation. Such a demonstration may help explaining the mechanisms involved in the reduction of fatal ischemic events in patients treated with angiotensin-converting enzyme inhibitors.
Limitations of the model of isolated, superfused, isometrically contracting human atrial trabeculae include the use of hypoxia rather than ischemia to initiate protection, recovery of contractile function as surrogate end-point, and the use of atrial rather than ventricular tissue.
Coronary Artery Bypass Surgery
Intermittent ischemia achieved by aortic cross-clamping in
a fibrillating heart during coronary artery bypass grafting has
been used as a clinical model of ischemic preconditioning. In
this model, the confounding effects due to collateral flow are overcome
by using global instead of regional ischemia. Recently, Yellon
et al12 examined the effect of two 3-minute
ischemic episodes, where each was followed by 2-minute
reperfusion on high energy phosphate metabolism during
10-minute cross-clamping. Distal coronary anastomosis was
performed during the cross-clamping. Myocardial biopsies taken
after the 10-minute ischemic insult exhibited a significantly
higher ATP content than was found in controls not previously exposed to
brief ischemic episodes, thus proving that the human
myocardium shows the typical biochemical features of
preconditioning observed by Murry et al1 in their classic
canine model of ischemic preconditioning. Yet, Perrault et
al13 have recently reported that 3-minute aortic
cross-clamping followed by 2-minute reperfusion before warm-blood
cardioplegic arrest during coronary artery bypass surgery fails
to provide any beneficial effect. Nevertheless, evidence that
preconditioning may offer patients protection against irreversible
myocyte injury comes from another study by Yellon and
coworkers.14 They showed a reduction of troponin T release
in patients exposed to two 3-minute periods of myocardial
ischemia at the beginning of the
revascularization operation. Furthermore, it has
been shown that in the setting of coronary artery bypass
surgery, adenosine15 and acadesine16
are effective in improving postoperative left ventricular
function. Taken together, these findings suggest that ischemic
preconditioning appears to occur in this human model with potentially
relevant beneficial clinical effects.
Coronary Angioplasty
The first formal study aimed at assessing adaptation to
ischemia during coronary angioplasty was reported by
Deutsch et al17 and involved 12 patients with an
isolated obstructive stenosis in the left anterior descending
coronary artery; they underwent 2 sequential 90-second balloon
inflations. In comparison with the initial balloon occlusion, the
second occlusion was characterized by less subjective anginal pain,
less ST-segment shift, and lower mean pulmonary artery
pressure, despite a reduction in cardiac vein flow and unchanged
coronary wedge pressure. These findings have been observed in
several other angioplasty studies,18 19 20 21 22 thus confirming
an adaptive response of the myocardium to repeated
ischemic episodes, akin to ischemic preconditioning. Of
note, some angioplasty studies failed to show adaptation to
ischemia during repeated coronary occlusions, probably
because they neglected some crucial methodological aspects, eg, short
balloon inflations of < 90 seconds, preinflation
ischemia, or inadequate end-points.23
Mechanisms of Adaptation to Ischemia
The adaptation to ischemia that was observed after
repeated coronary balloon occlusions may be a result of both
progressive collateral recruitment and ischemic
preconditioning. In order to determine the role of collateral
recruitment, we recently assessed changes in blood flow velocity in the
contralateral coronary artery during repeated balloon
occlusions by using a Doppler guide wire.22 We found
that coronary blood flow velocity significantly increased from
baseline to the end of the first inflation, whereas it exhibited a
modest increase during the second inflation in 
20% of the
patients, which failed to predict the changes in ST-segment shift or
cardiac pain severity. These findings are in agreement with those of
Kyriakidis et al,24 who assessed collateral recruitment by
using ipsilateral and contralateral injections of contrast medium.
Another major concern regarding the angioplasty model of preconditioning is that the electrocardiographic changes do not actually reflect ischemic preconditioning. Shattock et al25 addressed this problem by measuring ST-segment changes in open-chest pigs subjected to 2 cycles of 8-minute ischemia, induced by occlusion of left anterior descending coronary artery and 8-minute reperfusion followed by 1-hour ischemia and 2-hour reperfusion. They found that in the absence of a significant increase in collateral flow, ST-segment changes during the first 3 minutes of ischemia were smaller during the second and third ischemic cycle than during the first, and they concluded that ST-segment changes provide a reliable index of preconditioning during the first few minutes of coronary occlusion. More recently, in an open-chest rabbit model, Cohen et al26 found that the administration before repeated periods of coronary occlusions of drugs known to induce or prevent the classic form of preconditioning abolishes the attenuation of ST-segment changes.
Mechanisms of Ischemic Preconditioning
To establish whether the reduction of myocardial ischemia
observed in humans during coronary angioplasty after repeated
balloon inflations is a result of activation of
KATP channels, we randomized 20 consecutive
patients undergoing 1-vessel coronary angioplasty to receive 10
mg oral glibenclamide, a selective KATP channel
blocker, or placebo.18 We found that in
glibenclamide-treated patients, the mean ST-segment shift on the
intracoronary ECG during the second balloon inflation was
similar to that observed during the first inflation, and the severity
of cardiac pain was even greater. Conversely, in placebo-treated
patients, both the mean ST-segment shift and cardiac pain severity
during the second inflation were less than those during the first
inflation. Because the adaptation to ischemia observed during
brief repeated coronary occlusions was completely abolished by
pretreatment with glibenclamide, we suggested that in this human model
it is predominantly a result of ischemic preconditioning and is
mediated by KATP channels.
Adenosine receptors also appear to play an important role in
preconditioning during coronary angioplasty. In fact,
adenosine antagonists have been shown to prevent
the adaptation to ischemia during repeated balloon
inflations,19 20 whereas adenosine, independently
of its vasodilatory effect, is able to mimic it.21
Recently, we have shown that adaptation to ischemia during
coronary angioplasty is abolished by phentolamine in
the absence of collateral recruitment, thus suggesting that it is also
mediated by -adrenergic receptors.22
Finally, early results suggest that opioid receptors also seem to play a role in preconditioning during coronary angioplasty. In fact, morphine sulfate27 and naloxone28 have, respectively, been shown to mimic and prevent the adaptation to ischemia during repeated balloon inflations.
Exercise-Induced Ischemia (Warm-Up Phenomenon)
The warm-up phenomenon usually refers to the improved
performance exhibited by more than half of patients with
coronary artery disease following a first exercise
test.29 30 However, the mechanisms underlying the warm-up
phenomenon are still only partially known and somewhat
controversial.
Mechanisms of Adaptation to Exercise-Induced Ischemia
Okazaki et al29 demonstrated that in patients with a
single lesion of the left anterior descending coronary artery,
great cardiac vein flow is similar during the first and second exercise
stress test, thus suggesting that the warm-up phenomenon is not
accompanied by an increase in total myocardial blood flow.
Interestingly, myocardial oxygen consumption was reduced during the
second test, suggesting increased metabolic efficiency, a
feature of preconditioning. A role for preconditioning is also
supported by the demonstration that the time course of the warm-up
phenomenon is consistent with that of classic ischemic
preconditioning (lasting no longer than between 60 and 90
minutes).30 Indeed, we found that in patients with stable
angina undergoing 3 consecutive exercise tests, the warm-up phenomenon
observed within minutes of a first exercise test is a result of
adaptation to ischemia, whereas warm-up phenomenon observed 2
hours after the second exercise test is a result of a training effect
caused by peripheral mechanisms.30
Mechanisms of Ischemic Preconditioning
Adenosine receptors do not seem to play a major role in
the setting of the warm-up phenomenon. In fact, bamiphylline, a
selective antagonist of A1
adenosine receptors, at a dose previously shown to block
adaptation to ischemia during coronary
angioplasty,20 failed to prevent the warm-up
phenomenon.31
The involvement of KATP channels in the warm-up phenomenon is uncertain. In fact, KATP channel blockade by glibenclamide, given in the attempt to prevent the warm-up phenomenon at a dose previously shown to block adaptation to ischemia during coronary angioplasty,18 has yielded conflicting results.32 33 It is possible, therefore, that different mechanisms of ischemia might trigger the preconditioning state in different ways.
Preinfarction Angina
Recent studies have shown that patients with myocardial infarction
preceded by angina have smaller infarcts and a better in-hospital
outcome after thrombolytic therapy than patients
without preinfarction angina.34 35 36
At least 3 mechanisms may explain this difference between infarctions that are preceded by angina and those that are not: (1) coronary collaterals, (2) reperfusion rate, and (3) ischemic preconditioning.
Mechanisms of the Beneficial Effect of Preinfarction
Angina
Kloner et al 34 found that patients with angina
within 48 hours of myocardial infarction had a lower in-hospital death
rate and a smaller infarct size than patients without angina, despite a
similar development of coronary collateral vessels assessed at
angiography 90 minutes after myocardial infarction. This suggests that
preconditioning by preinfarction angina might render the
myocardium more resistant to infarction from the
subsequent prolonged ischemic episode.
Another attractive hypothesis about the protective role of preinfarction angina has been suggested by Andreotti et al.35 They compared the infarct size of patients with or without unstable angina during the week before myocardial infarction, taking into account the speed of recanalization. Interestingly, in patients with preinfarction angina, as compared with those without, thrombolytic therapy resulted in more rapid reperfusion and smaller infarcts, thus suggesting that the benefit of preinfarction angina on infarct size might depend on a speedier coronary thrombolysis in addition to, or perhaps instead of, preconditioning. Ishihara et al36 confirmed that reperfusion was more frequently achieved in patients with than in those without prodromal angina in the 24 hours before infarction, thus suggesting a more efficient response of the infarct-related artery to thrombolytic therapy in the former. However, they also demonstrated that prodromal angina in the 24 hours before infarction, but not angina occurring at an earlier time, was independently associated to a better 5-year outcome, thus suggesting a role for ischemic preconditioning.
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Clinical Implications |
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TopAbstractIntroductionIschemic Preconditioning:...Clinical ImplicationsReferences |
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The demonstration of preconditioning in humans has several important clinical implications. For instance, the increased mortality from cardiovascular causes observed in diabetic patients on sulfonylureas in the UGDP trial37 and the worse outcome of patients who are on sulfonylureas at the time of acute myocardial infarction38 might be due to blockade of preconditioning. These findings, if confirmed in prospective studies, might suggest that the treatment of diabetes in some high-risk coronary patients should be shifted from sulfonylureas to insulin. Similarly, the demonstration that adenosine receptor antagonists prevent ischemic preconditioning during coronary angioplasty19 20 and in vitro human8 studies suggests that methylxanthines should be used with caution in those patients with ischemic heart disease in whom ischemic preconditioning is likely to play an important cardioprotective role (ie, those with unstable angina and those who are undergoing coronary artery bypass surgery or coronary angioplasty).
Concerning the potential therapeutic applications of pharmacologic preconditioning, both KATP channel openers and adenosine or its analogues might limit the detrimental effects of myocardial ischemia. They may also have the potential to be used as cardioprotective agents during cardiac surgery and in the attempt to improve the preservation of explanted hearts before transplantation.
A tantalizing clinical application of pharmacologic preconditioning is in patients with acute myocardial infarction, in the attempt to slow down the progression of myocardial necrosis, thus increasing the time available for effective reperfusion. The exploitation of preconditioning, however, depends on the possibility of administering preconditioning drugs before ischemia, thus making this approach difficult in patients at low risk of myocardial infarction, such as those with chronic stable angina. Conversely, it is well known that patients with unstable angina or with a recent myocardial infarction have a higher risk of myocardial infarction in the few months after the initial ischemic episode.39 In this group of patients, the administration of drugs mimicking ischemic preconditioning in the period at increased risk might slow necrosis rate in those patients who will eventually develop an acute myocardial infarction, thus increasing the time available for reperfusion therapy. The myocardium of patients with unstable angina, however, might already be preconditioned by prior ischemic episodes, thus limiting the potential advantages of preconditioning drugs. Yet, it is reassuring that in the animal, preconditioning can be reinstated after the initial protection has waned.40 Another theoretical problem may be the development of tachyphylaxis to preconditioning agents. Indeed, Tsuchida et al41 have shown in a rabbit model that continuous infusion of a selective A1 adenosine receptor agonist led to downregulation of the signaling mechanism and loss of protection. However, more encouraging data have been obtained recently using a different dosing schedule, in which the same drug was administered to rabbits by intermittent dosing over a 10-day period with persistence of myocardial protection assessed 48 hours after the last dose.42
Finally, early reports have shown that the administration of preconditioning drugs as an adjunct to thrombolytic therapy may reduce infarct size43 and the incidence of tachyarrhythmias and myocardial ischemic episodes in unstable angina.44
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References |
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L. J. Velly, P. T. Canas, B. A. Guillet, C. N. Labrande, F. M. Masmejean, A. L. Nieoullon, F. M. Gouin, N. J. Bruder, and P. S. Pisano Early Anesthetic Preconditioning in Mixed Cortical Neuronal-Glial Cell Cultures Subjected to Oxygen-Glucose Deprivation: The Role of Adenosine Triphosphate Dependent Potassium Channels and Reactive Oxygen Species in Sevoflurane-Induced Neuroprotection Anesth. Analg., March 1, 2009; 108(3): 955 - 963. [Abstract] [Full Text] [PDF]
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 R. G. Katare, M. Ando, Y. Kakinuma, M. Arikawa, T. Handa, F. Yamasaki, and T. Sato Vagal nerve stimulation prevents reperfusion injury through inhibition of opening of mitochondrial permeability transition pore independent of the bradycardiac effect. J. Thorac. Cardiovasc. Surg., January 1, 2009; 137(1): 223 - 231. [Abstract] [Full Text] [PDF]
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 F. Crea, P. G. Camici, R. De Caterina, and G. A. Lanza CHAPTER 17 Chronic Ischaemic Heart Disease ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text] [PDF]
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L. Wang, N. Oka, M. Tropak, J. Callahan, J. Lee, G. Wilson, A. Redington, and C. A. Caldarone Remote ischemic preconditioning elaborates a transferable blood-borne effector that protects mitochondrial structure and function and preserves myocardial performance after neonatal cardioplegic arrest. J. Thorac. Cardiovasc. Surg., August 1, 2008; 136(2): 335 - 342. [Abstract] [Full Text] [PDF]
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 G. Niccoli, L. Altamura, A. Fabretti, G. A. Lanza, L. M. Biasucci, A. G. Rebuzzi, A. M. Leone, I. Porto, F. Burzotta, C. Trani, et al. Ethanol Abolishes Ischemic Preconditioning in Humans J. Am. Coll. Cardiol., January 22, 2008; 51(3): 271 - 275. [Abstract] [Full Text] [PDF]
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 B. Zhong and D. H. Wang TRPV1 gene knockout impairs preconditioning protection against myocardial injury in isolated perfused hearts in mice Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1791 - H1798. [Abstract] [Full Text] [PDF]
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J. F. Spear, S. K. Prabu, D. Galati, H. Raza, H. K. Anandatheerthavarada, and N. G. Avadhani beta1-Adrenoreceptor activation contributes to ischemia-reperfusion damage as well as playing a role in ischemic preconditioning Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2459 - H2466. [Abstract] [Full Text] [PDF]
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 M. Gheorghiade, G. Sopko, L. De Luca, E. J. Velazquez, J. D. Parker, P. F. Binkley, Z. Sadowski, K. S. Golba, D. L. Prior, J. L. Rouleau, et al. Navigating the Crossroads of Coronary Artery Disease and Heart Failure Circulation, September 12, 2006; 114(11): 1202 - 1213. [Full Text] [PDF]
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N. P. Riksen, Z. Zhou, W. J.G. Oyen, R. Jaspers, B. P. Ramakers, R. M.H.J. Brouwer, O. C. Boerman, N. Steinmetz, P. Smits, and G. A. Rongen Caffeine Prevents Protection in Two Human Models of Ischemic Preconditioning J. Am. Coll. Cardiol., August 15, 2006; 48(4): 700 - 707. [Abstract] [Full Text] [PDF]
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 S. Korom, S. Hillinger, M. Cardell, W. Zhai, Q. Tan, A. Dutly, B. Leskosek, and W. Weder Sildenafil extends survival and graft function in a large animal lung transplantation model Eur. J. Cardiothorac. Surg., March 1, 2006; 29(3): 288 - 293. [Abstract] [Full Text] [PDF]
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 S. K. Prabu, H. K. Anandatheerthavarada, H. Raza, S. Srinivasan, J. F. Spear, and N. G. Avadhani Protein Kinase A-mediated Phosphorylation Modulates Cytochrome c Oxidase Function and Augments Hypoxia and Myocardial Ischemia-related Injury J. Biol. Chem., January 27, 2006; 281(4): 2061 - 2070. [Abstract] [Full Text] [PDF]
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R. J. Domenech Preconditioning: A New Concept About the Benefit of Exercise Circulation, January 3, 2006; 113(1): e1 - e3. [Full Text] [PDF]
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 I. Ungi, T. Ungi, Z. Ruzsa, E. Nagy, Z. Zimmermann, T. Csont, and P. Ferdinandy Hypercholesterolemia Attenuates the Anti-ischemic Effect of Preconditioning During Coronary Angioplasty Chest, September 1, 2005; 128(3): 1623 - 1628. [Abstract] [Full Text] [PDF]
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C. Penna, G. Alloatti, S. Cappello, D. Gattullo, G. Berta, B. Mognetti, G. Losano, and P. Pagliaro Platelet-activating factor induces cardioprotection in isolated rat heart akin to ischemic preconditioning: role of phosphoinositide 3-kinase and protein kinase C activation Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2512 - H2520. [Abstract] [Full Text] [PDF]
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D. A. Liem, M. te Lintel Hekkert, O. C. Manintveld, F. Boomsma, P. D. Verdouw, and D. J. Duncker Myocardium tolerant to an adenosine-dependent ischemic preconditioning stimulus can still be protected by stimuli that employ alternative signaling pathways Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1165 - H1172. [Abstract] [Full Text] [PDF]
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T. Gori, S. Sicuro, S. Dragoni, G. Donati, S. Forconi, and J. D. Parker Sildenafil Prevents Endothelial Dysfunction Induced by Ischemia and Reperfusion via Opening of Adenosine Triphosphate-Sensitive Potassium Channels: A Human In Vivo Study Circulation, February 15, 2005; 111(6): 742 - 746. [Abstract] [Full Text] [PDF]
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 C. Garcia, K. Julier, L. Bestmann, A. Zollinger, L. K. von Segesser, T. Pasch, D. R. Spahn, and M. Zaugg Preconditioning with sevoflurane decreases PECAM-1 expression and improves one-year cardiovascular outcome in coronary artery bypass graft surgery Br. J. Anaesth., February 1, 2005; 94(2): 159 - 165. [Abstract] [Full Text] [PDF]
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G. A. Rongen, W. J.G. Oyen, B. P. Ramakers, N. P. Riksen, O. C. Boerman, N. Steinmetz, and P. Smits Annexin A5 Scintigraphy of Forearm as a Novel In Vivo Model of Skeletal Muscle Preconditioning in Humans Circulation, January 18, 2005; 111(2): 173 - 178. [Abstract] [Full Text] [PDF]
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H. Barthel, D. Ebel, J. Mullenheim, D. Obal, B. Preckel, and W. Schlack Effect of lidocaine on ischaemic preconditioning in isolated rat heart Br. J. Anaesth., November 1, 2004; 93(5): 698 - 704. [Abstract] [Full Text] [PDF]
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T. Waldow, K. Alexiou, W. Witt, F. M. Wagner, V. Gulielmos, K. Matschke, and M. Knaut Attenuation of Reperfusion-Induced Systemic Inflammation by Preconditioning With Nitric Oxide in an In Situ Porcine Model of Normothermic Lung Ischemia Chest, June 1, 2004; 125(6): 2253 - 2259. [Abstract] [Full Text] [PDF]
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 A. Arboix, M. Tarruella, L. Garcia-Eroles, M. Oliveres, C. Miquel, M. Balcells, and C. Targa Ischemic stroke in patients with intermittent claudication: a clinical study of 142 cases Vascular Medicine, February 1, 2004; 9(1): 13 - 17. [Abstract] [PDF]
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 D. M. YELLON and J. M. DOWNEY Preconditioning the Myocardium: From Cellular Physiology to Clinical Cardiology Physiol Rev, October 1, 2003; 83(4): 1113 - 1151. [Abstract] [Full Text] [PDF]
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T. Miura Myocardial response to ischemic preconditioning: is it a novel predictor of prognosis? J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1004 - 1006. [Full Text] [PDF]
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M. A. Leesar, M. F. Stoddard, Y.-T. Xuan, X.-L. Tang, and R. Bolli Nonelectrocardiographic evidence that both ischemic preconditioning and adenosine preconditioning exist in humans J. Am. Coll. Cardiol., August 6, 2003; 42(3): 437 - 445. [Abstract] [Full Text] [PDF]
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 B. Bartling, I. Friedrich, R.-E. Silber, and A. Simm Ischemic preconditioning is not cardioprotective in senescent human myocardium Ann. Thorac. Surg., July 1, 2003; 76(1): 105 - 111. [Abstract] [Full Text] [PDF]
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P. D. Lambiase, R. J. Edwards, M. R. Cusack, C. A. Bucknall, S. R. Redwood, and M. S. Marber Exercise-induced ischemia initiates the second window of protection in humans independent of collateral recruitment J. Am. Coll. Cardiol., April 2, 2003; 41(7): 1174 - 1182. [Abstract] [Full Text] [PDF]
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 C. Weinbrenner, M. Nelles, N. Herzog, L. Sarvary, and R. H Strasser Remote preconditioning by infrarenal occlusion of the aorta protects the heart from infarction: a newly identified non-neuronal but PKC-dependent pathway Cardiovasc Res, August 15, 2002; 55(3): 590 - 601. [Abstract] [Full Text] [PDF]
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S. C. Smith Jr, D. Faxon, W. Cascio, H. Schaff, T. Gardner, A. Jacobs, S. Nissen, and R. Stouffer Prevention Conference VI: Diabetes and Cardiovascular Disease: Writing Group VI: Revascularization in Diabetic Patients Circulation, May 7, 2002; 105 (18): e165 - e169. [Full Text] [PDF]
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 F Tomai Warm up phenomenon and preconditioning in clinical practice Heart, February 1, 2002; 87(2): 99 - 100. [Full Text] [PDF]
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P. J. Gheeraert, J. P. S. Henriques, M. L. De Buyzere, M. De Pauw, Y. Taeymans, and F. Zijlstra Preinfarction angina protects against out-of-hospital ventricular fibrillation in patients with acute occlusion of the left coronary artery J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1369 - 1374. [Abstract] [Full Text] [PDF]
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 C. D. Raeburn, J. C. Cleveland Jr, M. A. Zimmerman, and A. H. Harken Organ Preconditioning Arch Surg, November 1, 2001; 136(11): 1263 - 1266. [Abstract] [Full Text] [PDF]
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M. A. Leesar, M. F. Stoddard, B. Dawn, V. G. Jasti, R. Masden, and R. Bolli Delayed Preconditioning-Mimetic Action of Nitroglycerin in Patients Undergoing Coronary Angioplasty Circulation, June 19, 2001; 103(24): 2935 - 2941. [Abstract] [Full Text] [PDF]
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 K. Nandagopal, T. M. Dawson, and V. L. Dawson Critical Role for Nitric Oxide Signaling in Cardiac and Neuronal Ischemic Preconditioning and Tolerance J. Pharmacol. Exp. Ther., April 12, 2001; 297(2): 474 - 478. [Abstract] [Full Text]
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S. Salvi Protecting the Myocardium From Ischemic Injury : A Critical Role for {{alpha}}1-Adrenoreceptors? Chest, April 1, 2001; 119(4): 1242 - 1249. [Abstract] [Full Text] [PDF]
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 J.-C. COPIN, Y. GASCHE, Y. LI, and P. H. CHAN Prolonged hypoxia during cell development protects mature manganese superoxide dismutase-deficient astrocytes from damage by oxidative stress FASEB J, February 1, 2001; 15(2): 525 - 534. [Abstract] [Full Text] [PDF]
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K. Lu, H. Otani, T. Yamamura, Y. Nakao, R. Hattori, H. Ninomiya, M. Osako, and H. Imamura Protein kinase C isoform-dependent myocardial protection by ischemic preconditioning and potassium cardioplegia J. Thorac. Cardiovasc. Surg., January 1, 2001; 121(1): 0137 - 148. [Abstract] [Full Text] [PDF]
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R. M Mohan and D. J Paterson Activation of sulphonylurea-sensitive channels and the NO-cGMP pathway decreases the heart rate response to sympathetic nerve stimulation Cardiovasc Res, July 1, 2000; 47(1): 81 - 89. [Abstract] [Full Text] [PDF]
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 M.-C. Wellner-Kienitz, K. Bender, T. Meyer, M. Bunemann, and L. Pott Overexpressed A1 Adenosine Receptors Reduce Activation of Acetylcholine-Sensitive K+ Current by Native Muscarinic M2 Receptors in Rat Atrial Myocytes Circ. Res., March 31, 2000; 86(6): 643 - 648. [Abstract] [Full Text] [PDF]
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 M. Gonzalez-Zulueta, A. B. Feldman, L. J. Klesse, R. G. Kalb, J. F. Dillman, L. F. Parada, T. M. Dawson, and V. L. Dawson Requirement for nitric oxide activation of p21ras/extracellular regulated kinase in neuronal ischemic preconditioning PNAS, January 4, 2000; 97(1): 436 - 441. [Abstract] [Full Text] [PDF]
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M. Birincioglu, X.-M. Yang, S. D. Critz, M. V. Cohen, and J. M. Downey S-T segment voltage during sequential coronary occlusions is an unreliable marker of preconditioning Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2435 - H2441. [Abstract] [Full Text] [PDF]
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