Skip to main content
  • American Heart Association
  • Science Volunteer
  • Warning Signs
  • Advanced Search
  • Donate

  • Home
  • About this Journal
    • Editorial Board
    • Meet the Editors
    • Editorial Manifesto
    • Impact Factor
    • Journal History
    • General Statistics
  • All Issues
  • Subjects
    • All Subjects
    • Arrhythmia and Electrophysiology
    • Basic, Translational, and Clinical Research
    • Critical Care and Resuscitation
    • Epidemiology, Lifestyle, and Prevention
    • Genetics
    • Heart Failure and Cardiac Disease
    • Hypertension
    • Imaging and Diagnostic Testing
    • Intervention, Surgery, Transplantation
    • Quality and Outcomes
    • Stroke
    • Vascular Disease
  • Browse Features
    • Circulation Research Profiles
    • Trainees & Young Investigators
    • Research Around the World
    • News & Views
    • The NHLBI Page
    • Viewpoints
    • Compendia
    • Reviews
    • Recent Review Series
    • Profiles in Cardiovascular Science
    • Leaders in Cardiovascular Science
    • Commentaries on Cutting Edge Science
    • AHA/BCVS Scientific Statements
    • Abstract Supplements
    • Circulation Research Classics
    • In This Issue Archive
    • Anthology of Images
  • Resources
    • Online Submission/Peer Review
    • Why Submit to Circulation Research
    • Instructions for Authors
    • → Article Types
    • → Manuscript Preparation
    • → Submission Tips
    • → Journal Policies
    • Circulation Research Awards
    • Image Gallery
    • Council on Basic Cardiovascular Sciences
    • Customer Service & Ordering Info
    • International Users
  • AHA Journals
    • AHA Journals Home
    • Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)
    • Circulation
    • → Circ: Arrhythmia and Electrophysiology
    • → Circ: Genomic and Precision Medicine
    • → Circ: Cardiovascular Imaging
    • → Circ: Cardiovascular Interventions
    • → Circ: Cardiovascular Quality & Outcomes
    • → Circ: Heart Failure
    • Circulation Research
    • Hypertension
    • Stroke
    • Journal of the American Heart Association
  • Impact Factor 13.965
  • Facebook
  • Twitter

  • My alerts
  • Sign In
  • Join

  • Advanced search

Header Publisher Menu

  • American Heart Association
  • Science Volunteer
  • Warning Signs
  • Advanced Search
  • Donate

Circulation Research

  • My alerts
  • Sign In
  • Join

  • Impact Factor 13.965
  • Facebook
  • Twitter
  • Home
  • About this Journal
    • Editorial Board
    • Meet the Editors
    • Editorial Manifesto
    • Impact Factor
    • Journal History
    • General Statistics
  • All Issues
  • Subjects
    • All Subjects
    • Arrhythmia and Electrophysiology
    • Basic, Translational, and Clinical Research
    • Critical Care and Resuscitation
    • Epidemiology, Lifestyle, and Prevention
    • Genetics
    • Heart Failure and Cardiac Disease
    • Hypertension
    • Imaging and Diagnostic Testing
    • Intervention, Surgery, Transplantation
    • Quality and Outcomes
    • Stroke
    • Vascular Disease
  • Browse Features
    • Circulation Research Profiles
    • Trainees & Young Investigators
    • Research Around the World
    • News & Views
    • The NHLBI Page
    • Viewpoints
    • Compendia
    • Reviews
    • Recent Review Series
    • Profiles in Cardiovascular Science
    • Leaders in Cardiovascular Science
    • Commentaries on Cutting Edge Science
    • AHA/BCVS Scientific Statements
    • Abstract Supplements
    • Circulation Research Classics
    • In This Issue Archive
    • Anthology of Images
  • Resources
    • Online Submission/Peer Review
    • Why Submit to Circulation Research
    • Instructions for Authors
    • → Article Types
    • → Manuscript Preparation
    • → Submission Tips
    • → Journal Policies
    • Circulation Research Awards
    • Image Gallery
    • Council on Basic Cardiovascular Sciences
    • Customer Service & Ordering Info
    • International Users
  • AHA Journals
    • AHA Journals Home
    • Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)
    • Circulation
    • → Circ: Arrhythmia and Electrophysiology
    • → Circ: Genomic and Precision Medicine
    • → Circ: Cardiovascular Imaging
    • → Circ: Cardiovascular Interventions
    • → Circ: Cardiovascular Quality & Outcomes
    • → Circ: Heart Failure
    • Circulation Research
    • Hypertension
    • Stroke
    • Journal of the American Heart Association
Review

The Coronary Circulation as a Target of Cardioprotection

Gerd Heusch
Download PDF
https://doi.org/10.1161/CIRCRESAHA.116.308640
Circulation Research. 2016;118:1643-1658
Originally published May 12, 2016
Gerd Heusch
From the Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, University of Essen, Essen, Germany.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Tables
  • Info & Metrics

Jump to

  • Article
    • Abstract
    • Coronary Circulation as a Determinant of Myocardial Ischemic Injury
    • Coronary Circulation as a Determinant of Reperfusion and Reperfusion Injury
    • Manifestations of Myocardial Ischemia/Reperfusion Injury in the Coronary Circulation
    • Coronary Vascular Protection by Ischemic Preconditioning
    • Coronary Vascular Protection by Ischemic Postconditioning
    • Coronary Vascular Protection by Remote Ischemic Conditioning
    • Coronary Vascular Protection by Drugs and Cardioprotective Interventions
    • Coronary Microvascular Injury: Cause or Consequence of Myocardial Ischemia/Reperfusion
    • Sources of Funding
    • Disclosures
    • Footnotes
    • References
  • Figures & Tables
  • Info & Metrics
  • eLetters
Loading

Abstract

The atherosclerotic coronary vasculature is not only the culprit but also a victim of myocardial ischemia/reperfusion injury. Manifestations of such injury are increased vascular permeability and edema, endothelial dysfunction and impaired vasomotion, microembolization of atherothrombotic debris, stasis with intravascular cell aggregates, and finally, in its most severe form, capillary destruction with hemorrhage. In animal experiments, local and remote ischemic pre- and postconditioning not only reduce infarct size but also these manifestations of coronary vascular injury, as do drugs which recruit signal transduction steps of conditioning. Clinically, no-reflow is frequently seen after interventional reperfusion, and it carries an adverse prognosis. The translation of cardioprotective interventions to clinical practice has been difficult to date. Only 4 drugs (brain natriuretic peptide, exenatide, metoprolol, and esmolol) stand unchallenged to date in reducing infarct size in patients with reperfused acute myocardial infarction; unfortunately, for these drugs, no information on their impact on the ischemic/reperfused coronary circulation is available.

  • coronary artery disease
  • coronary occlusion
  • hemorrhage
  • myocardial infarction
  • reperfusion injury

Myocardial ischemia/reperfusion injury affects not only the cardiomyocyte compartment but also all other cellular compartments, and the coronary circulation has a central role in it.1,2 Acute myocardial infarction most often arises from atherosclerotic plaque rupture/erosion with superimposed thrombosis (type 1 myocardial infarction). However, in the absence of coronary atherosclerosis, coronary vasospasm and endothelial dysfunction may also precipitate acute myocardial infarction (type 2).3 Reperfusion of the occluded coronary artery with restoration of coronary blood flow not only terminates myocardial ischemia but also inflicts additional injury,4–6 and interventional or surgical revascularization may actually induce periprocedural myocardial infarction (types 4 and 5 myocardial infarction). The spatial and temporal evolution of coronary occlusion and reperfusion determine not only the size of the affected myocardial region but also the nature of the outcome from myocardial ischemia/reperfusion, that is, reversible (stunning) or irreversible (infarction) injury and, vice versa, also protection from injury (hibernation and conditioning).

Cardioprotective interventions reduce myocardial ischemia/reperfusion injury, notably infarct size, but also arrhythmias, left ventricular dysfunction, and coronary vascular impairment. A complex signal transduction cascade underlies the cardioprotective effects of ischemic preconditioning, ischemic postconditioning, and remote ischemic conditioning.7 A variety of drugs that often recruit signaling steps of conditioning strategies have been used to achieve cardioprotection. The translation of cardioprotection from animal experiments to clinical practice has been difficult and largely disappointing to date, despite several positive proof-of-concept studies in humans.8 Neglect of the coronary circulation as a victim of myocardial ischemia/reperfusion injury and as a target for cardioprotection may have contributed to the lack of translation of cardioprotection to clinical practice.2

A particular problem is acute myocardial infarction in women.9 On the one hand, the female heart is more resistant to myocardial ischemia/reperfusion than the male heart.10 On the other hand, women have nonobstructive coronary artery disease more often than men, and coronary vasomotion (coronary vasospasm, endothelial dysfunction, and microvascular dysfunction) may play a greater role in precipitating acute myocardial infarction in women.11

Coronary Circulation as a Determinant of Myocardial Ischemic Injury

The perfusion territory of the coronary artery distal to the site of the occlusion is the area at risk of infarction because the coronary arteries are functional end arteries. Within a given area at risk, both the duration and the severity of coronary blood flow reduction determine the nature and amount of injury.12,13 A complete coronary occlusion of <20-minute duration results in reversible injury, that is, contractile dysfunction with a slow, but complete recovery during reperfusion, a phenomenon called myocardial stunning.14,15 The underlying mechanisms of the prolonged contractile dysfunction relate to the enhanced formation of reactive oxygen species during early reperfusion16 and impaired excitation–contraction coupling after oxidative modification of the sarcoplasmic reticulum and the contractile proteins.17 Repeated coronary occlusion of short duration or prolonged moderate reduction in coronary blood flow results in hibernating myocardium, a phenomenon of reduced contractile function with retained viability and thus eventual recovery after reperfusion. Hibernating myocardium displays signs of both injury (loss of contractile proteins, small doughnut-like mitochondria, and fibrosis) and adaptation (short-term energetic recovery, altered expression of mitochondrial proteins, and proteins related to cardioprotection).18,19 When the reduction in coronary blood flow is severe and lasts longer than 20 to 40 minutes, infarction in larger mammals develops first in the inner subendocardial layers of the core of the area at risk and then spreads in a wavefront to the outer subepicardial layers and the borders of the area at risk over time. The wavefront of infarct development reflects the lateral and transmural distribution of coronary blood flow, which is less in the inner than in the outer layers of the myocardium and less in the core than in the borders of the area at risk.20,21 The evolution of infarction varies with species and depends on the existence and extent of a collateral circulation.22 Rodents have a high heart rate and rapid development of infarction; only in guinea pigs there is such an extensive collateral circulation that no infarction develops for hours of coronary occlusion.22 Dogs have a well-developed native collateral circulation, and infarction starts after 40-minute coronary occlusion and spreads to affect 70% of the area at risk after 6 hours20,21; in dogs, therefore, infarct size is best quantified as a fraction of the area at risk and normalized to the residual blood flow.12 Pigs have a negligible native collateral circulation, and infarction starts after 15 to 35-minute coronary occlusion and affects 80% of the area at risk after 60 to 180 minutes.23,24 Primates have few innate collaterals but are relatively resistant to myocardial ischemia; there is no infarction after 40- to 60-minute coronary occlusion, and even after 90-minute coronary occlusion, infarct size is smaller than that in pigs.25 Apart from such species differences in the native collateral circulation, coronary vasomotor mechanisms also differ between species. Pigs, in contrast to dogs, respond to acetylcholine with coronary vasoconstriction rather than vasodilation,26 and pigs have only negligible α-adrenergic coronary vasoconstriction.27 With respect to such coronary vasomotor mechanisms, humans are closer to dogs than to pigs28; however, in the presence of coronary atherosclerosis in humans, the response to acetylcholine may also be reversed from vasodilation to vasoconstriction.29 Fortunately, infarct development in humans is slower than that in the above-mentioned large mammals. Even after 4 to 6 hours of coronary occlusion, 30% to 50% of the area at risk remain viable and thus salvageable, as one can estimate from magnetic resonance imaging (MRI) and from the amount of salvage by reperfusion.30–32 Salvageable myocardium remains even after 12 hours from symptom onset,33 and its salvage improves patients’ prognosis.34 It is unclear at present to what extent the resistance of the diseased human heart is attributable to a developed collateral circulation at the time of infarction, as in the native dog heart, or reflects an inherently greater resistance to ischemic injury, as in the primate heart, or reflects preceding episodes of myocardial ischemia/reperfusion with a preconditioning effect. Also, effective drug treatment (eg, by concomitant β-blockade, renin–angiotensin system inhibition, statins, or P2Y12 antagonists) may induce pre-existing cardioprotection and attenuate the consequences of acute myocardial ischemia/reperfusion.35 In contrast to previous notions, the hemodynamic situation has little impact on the development of myocardial infarction; only heart rate determines infarct progression to some extent.36 Variations in coronary blood flow not only determine the nature and extent of myocardial injury but paradoxically also protection from it. Repeated brief episodes of coronary occlusion preceding a prolonged coronary occlusion with reperfusion reduce infarct size, that is, there is ischemic preconditioning.37 Likewise, repeated brief coronary occlusion during early reperfusion reduces infarct size, that is, there is ischemic postconditioning.38

Coronary Circulation as a Determinant of Reperfusion and Reperfusion Injury

Although today it is unequivocally clear that timely reperfusion of an occluded coronary artery is the only way to rescue myocardium from impending infarction, this notion is a little more than 40 years old and goes back to the study by Ross and collaborators39,40 who first reported that reperfusion after 180-minute coronary occlusion reduced infarct size in dogs. These findings were quickly translated to humans with acute myocardial infarction who were reperfused by thrombolysis or percutaneous coronary interventions (PCIs).13,41–43 Even before the benefits of reperfusion were established, the dark side of coronary reperfusion became apparent, when Krug et al44 and then Kloner et al45 reported the coronary no-reflow phenomenon. And again only a few years later, Reimer et al20 and Reimer and Jennings21 reported in a series of detailed dog studies that signs of irreversible myocardial injury, such as rupture of the sarcolemma, became particularly manifest during reperfusion; at that time, it was not clear whether the irreversible injury was caused by reperfusion or only became better manifest during reperfusion. The long debate on the existence of lethal reperfusion injury46 was finally ended by the recognition of the ischemic postconditioning phenomenon when Vinten-Johansen and colleagues38 reported that repeated coronary reocclusion during early reperfusion reduced infarct size in dogs, and these findings were quickly confirmed in patients with reperfused acute myocardial infarction.47,48 The fact that a modified procedure of reperfusion could indeed attenuate irreversible injury once again revived earlier studies on gentle reperfusion,49 that is, the reduction of functional and morphological signs of injury by reperfusion at reduced perfusion pressure50 or reduced coronary blood flow.51 With the unequivocal notion that reperfusion is both mandatory for salvage from impending infarction and it causes irreversible injury per se, a complex picture arises in that both ischemia and reperfusion contribute to the ultimate injury, but their individual contribution to ultimate injury depends on the duration and severity of coronary blood flow reduction.52 Whereas ischemic injury increases with the severity and the duration of coronary blood flow reduction, there is a maximum of reperfusion injury at more moderate ischemic injury (Figure 1).

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

Infarct size as a function of duration of ischemia and residual/collateral blood flow. With longer ischemia duration and less blood flow, ischemia-induced injury increases. The greater the ischemia-induced injury, the less myocardium is salvaged but also the less is damaged by reperfusion. Reprinted from Heusch.52 Copyright ©2013, American Physiological Society.

Technically, in the experiment, infarct size is best quantified by triphenyl tetrazolium chloride staining after sufficient reperfusion with washout of reductive equivalents.53,54 Infarct size is best normalized to the area at risk which is delineated by a water-soluble dye injected into the left atrium after reocclusion of the coronary artery at its culprit site (Figure 2). The area of no-reflow is delineated by injection of thioflavin S into the left atrium, which stains endothelial cells, such that lack of thioflavin fluorescence reflects no-reflow zones.55 In patients, infarct size can be estimated from cardiac enzyme release or imaging, notably late gadolinium enhancement in MRI. No-reflow is primarily an angiographic diagnosis immediately after reopening of the culprit coronary occlusion, and it is quantified by reduced thrombolysis in myocardial infarction (TIMI) flow grade, increased TIMI frame count, and reduced myocardial blush grade.56–59 More recently, microvascular obstruction is visualized by MRI as lack of contrast within gadolinium-enhanced areas. Area of risk can be best visualized by scintigraphy, and there are problems in estimating area at risk with T2-weighted edema imaging in MRI (see below).

Figure 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2.

Typical example for delineation of area at risk by Patent blue (left), of infarction by triphenyl tetrazolium chloride staining (middle), and of no-reflow by thioflavin S fluorescence (right). The no-reflow area was encircled by an incision.

Manifestations of Myocardial Ischemia/Reperfusion Injury in the Coronary Circulation

The manifestations of myocardial ischemia/reperfusion in the coronary circulation go from mild and reversible functional impairment to severe and irreversible destruction (Figure 3).

Figure 3.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 3.

Schematic diagram with the different manifestations of coronary vascular injury during acute myocardial ischemia/reperfusion and the protective interventions that attenuate these manifestations. IP indicates ischemic preconditioning; POCO, ischemic postconditioning; and RIC, remote ischemic conditioning.

Vascular Permeability: Edema

Edema develops quickly within minutes of acute myocardial ischemia60–64 and is both intracellular and interstitial. Intracellular edema develops in cardiomyocytes and endothelial cells largely as a consequence of the rapidly developing energetic deficit and the reduced function of energy-dependent ion pumps.65 Interstitial edema develops as a consequence of increased interstitial osmolarity from increased ion and catabolite concentrations and a dysfunction of the endothelial barrier function during myocardial ischemia.65 The endothelial barrier function is made up by the glycocalyx,66 endothelial cells, and pericytes (particularly at the postcapillary venules67). Endothelial cytoskeletal derangement and hypercontracture induce gap formation,68–71 which is enhanced by extracellular adenosine but attenuated by extracellular ATP.72 Degradation of the glycocalyx also contributes to reduced endothelial barrier function and edema formation66,73,74; tumor necrosis factor α is an important mediator of glycocalyx degradation,75 and glycocalyx degradation also promotes leukocyte76 and platelet adherence.77 Exogenous nitric oxide preserves vascular integrity and attenuates edema formation through protection of the glycocalyx.78 On reperfusion, interstitial edema is greatly enhanced by reactive hyperemia and the rapid washout of osmotically active molecules from the intravascular space. The cellular (as a consequence of a reversed acidosis and intracellular sodium and calcium overload) and interstitial edema development during reperfusion follows a bimodal pattern where an initial maximum of water content after 120 minutes is associated with a beginning leukocyte infiltration, and a secondary peak after 7 days is associated with enhanced collagen deposition.79 Edema during reperfusion has been proposed to reflect the area at risk on MRI,80 but edema may artifactually increase the area at risk,81 and a bimodal pattern of edema further questions the use of T2-weighted edema measurement for area at risk delineation.82 Myocardial edema not only is a consequence of sustained myocardial ischemia/reperfusion but also contributes to the impairment of microvascular perfusion by extravascular compression.83,84

Vasomotion

The coronary microcirculation distal to a severe coronary stenosis or coronary occlusion has traditionally been considered as maximally dilated after exhaustion of autoregulatory reserve. However, even during myocardial ischemia which limits regional contractile function, a pharmacologically recruitable vasodilator reserve persists.85,86 Reactive oxygen species contributes to the endothelial dysfunction and consequent impairment of coronary vasomotion.87 The impairment of endothelium-mediated vasodilation correlates to the severity of myocardial injury, that is, it is greater in infarcted than in reversibly injured myocardium (Figure 4).88 During myocardial ischemia/reperfusion, the coronary microcirculation remains responsive to vasoconstrictor mediators, notably α-adrenergic coronary vasoconstriction.89,90 Such α-adrenergic coronary constrictor impact is also seen in humans with chronic stable angina91 and during PCIs.92,93 The release of vasoconstrictor substances, such as thromboxane, serotonin,94,95 and endothelin96 from the rupturing culprit lesion into the microcirculation, in conjunction with the impairment of endothelial function by ischemia/reperfusion per se60,87,88,97,98 or by tumor necrosis factor α,95 can contribute to such enhanced vasoconstrictor responsiveness during myocardial ischemia/reperfusion. With more prolonged ischemia in hibernating myocardium, there is structural remodeling of the microvasculature with hypertrophy of smaller and atrophy of larger vessels, reduced vascular distensibility, and increased vasoconstriction in response to endothelin.99,100

Figure 4.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 4.

Increase in regional myocardial blood flow in response to intracoronary acetylcholine after 15- vs 60-minute coronary occlusion in dogs, separately for subendocardial, midmyocardial, and subepicardial layers. After 60-minute coronary occlusion, the vasodilator response to acetylcholine is depressed, more in subendocardial than in subepicardial layers and more in infarcted (triphenyl tetrazolium chloride [TTC] negative) than in viable (TTC positive) myocardium. Reprinted from Ehring et al.88 Copyright ©1995, the American Physiological Society.

Microembolization

Plaque fissure or rupture occur spontaneously and are induced traumatically/iatrogenically by PCIs. Atherosclerotic debris with superimposed thrombotic material is then dislodged and embolized into the coronary microcirculation101 where it induces patchy microinfarcts with an inflammatory reaction.102 Such microinfarcts add to the infarct size caused by sustained coronary occlusion with reperfusion101,103,104 and impair coronary dilator reserve.105,106 In patients, coronary microembolization is particularly seen with PCIs in saphenous vein bypass grafts, and it is here that protection devices are useful to prevent atherothrombotic debris from embolizing into the microcirculation.107,108

Stasis and Intravascular Cellular Aggregates

Myocardial ischemia and reperfusion increase the expression of adhesion molecules, such as intercellular adhesion molecules, vascular cell adhesion molecules, and selectins, on endothelium and circulating cells and thereby promote the interaction of platelets, leukocytes, and endothelium and the adherence of platelet aggregates and platelet–leukocyte aggregates to the endothelium.109–115 Such aggregates are either released from the epicardial atherosclerotic culprit lesion and dislodged into the microcirculation or formed in the coronary microcirculation. These cellular aggregates contribute to the impairment of microvascular perfusion. In pronounced forms of no-reflow, also typical erythrocyte aggregates are found that block the capillaries.116

Capillary Destruction: Hemorrhage

The most severe forms of coronary microvascular injury from myocardial ischemia/reperfusion, as already detailed in the original reports of coronary no-reflow by Krug et al44 and Kloner et al,45 are the massive swelling of capillary endothelial cells with consequent rupture of the vascular wall and leakage of circulating cells into the interstitium, that is, hemorrhage. Hemorrhage is associated with severe ischemia during coronary occlusion and with severe myocardial necrosis.117,118 Hemorrhage in reperfused myocardial infarction has received more attention by MRI because the hemoglobin catabolites are paramagnetic and attenuate the T2-weighted signal intensity within an otherwise high T2-weighted signal area (edema).119–122 No-reflow is seen in ≈35% of patients with optimal reperfusion therapy, and its incidence increases with the delay of reperfusion.123,124 No-reflow and hemorrhage carry an adverse prognosis for patients with reperfused myocardial infarction.124–126

The above manifestations of coronary vascular injury by myocardial ischemia/reperfusion are attenuated by local ischemic pre- and postconditioning, as well as by remote ischemic conditioning and by various cardioprotective drugs and interventions. However, not for every manifestation of coronary vascular injury information is available for every form of cardioprotection. Often, only the resulting no-reflow or the area of no-reflow was assessed. In particular, data for patients with myocardial ischemia/reperfusion are not systematically available.

Coronary Vascular Protection by Ischemic Preconditioning

Ischemic preconditioning protects endothelial function and structure from myocardial ischemia/reperfusion injury.127 In Langendorff-perfused mouse hearts, ischemic preconditioning by 1 cycle of 2-minute global ischemia/5-minute reperfusion before 40-minute sustained global ischemia with reperfusion preserved the ultrastructure of endothelial tight junctions and attenuated edema.70 Similarly, ischemic preconditioning in rats attenuated the increase in microvascular permeability and edema development with sustained ischemia/reperfusion.128 Ischemic preconditioning with 5-minute coronary occlusion/10-minute reperfusion before 60-minute coronary occlusion and reperfusion in dogs reduced not only infarct size but also edema.38 An early study in anesthetized dogs found no protection by ischemic preconditioning on endothelium-dependent coronary vasodilation in response to acetylcholine and on low-reflow after 60-minute coronary occlusion with reperfusion.129 Another study in dogs with 60-minute coronary occlusion and reperfusion also reported no improvement in the coronary vasodilator response to acetylcholine but improved reflow with ischemic preconditioning by 2 cycles of 5-minute myocardial ischemia/5-minute reperfusion.130 However, the majority of subsequent studies reported protection by ischemic preconditioning on endothelial function, as assessed by endothelium-dependent coronary vasodilation in response to acetylcholine, serotonin, or ADP in rats,131–133 guinea pigs,134 dogs,135,136 pigs,137 and goats.138 Mechanistically, the preservation of endothelial function by ischemic preconditioning was related to adenosine,132,136 bradykinin,133 and nitric oxide.138,139 The preservation of endothelial function by ischemic preconditioning became apparent not only as improved endothelium-dependent coronary vasodilation but also as reduced leukocyte adherence.134,135,139 Coronary endothelial function recovers only slowly after myocardial ischemia/reperfusion and is still depressed after 1 month, but ischemic preconditioning also improves endothelium-dependent coronary vasodilation in response to acetylcholine and endothelial ultrastructure after 1 month.140 Vice versa, delayed ischemic preconditioning 24 hours before the sustained myocardial ischemia/reperfusion increases the activity of endothelial nitric oxide synthase, which mediates preservation of coronary vasodilator response to acetylcholine, carbachol, and bradykinin.141,142 Reactive oxygen species formation, although detrimental acutely for endothelium-dependent coronary vasodilation in response to acetylcholine, is mandatory for the delayed protection by ischemic preconditioning.143 Ischemic preconditioning not only preserves endothelium-dependent coronary vasodilation but also attenuates the enhanced coronary vasoconstrictor tone after hyperkalemic cardioplegia through a ATP-dependent potassium channel–dependent mechanism in coronary vascular smooth muscle cells.144 Coronary microembolization with release of adenosine into the coronary vasculature does not induce acute preconditioning and reduce infarct size or, conversely, interfere with protection by ischemic preconditioning.103,145 Somewhat paradoxically, the increase in tumor necrosis factor α expression secondary to coronary microembolization can induce delayed protection and reduce infarct size from subsequent coronary occlusion/reperfusion,146 such that the actual impact of coronary microembolization on infarct size depends critically on timing and is difficult to predict. Preinfarction angina is considered a clinical correlate of ischemic preconditioning.147,148 Patients with preinfarction angina have reduced platelet reactivity, less monocyte–platelet aggregates,149 and better reflow and coronary flow reserve during reperfusion.150,151

Coronary Vascular Protection by Ischemic Postconditioning

The classical study by Vinten-Johansen and coworkers38 in dogs undergoing an ischemic postconditioning protocol of 3 cycles of 30-second coronary reocclusion/30-second reperfusion at immediate reperfusion after 60-minute coronary occlusion reported not only reduced infarct size but also reduced edema; both infarct size and edema were reduced to the same extent as with ischemic preconditioning. Neither the reduction of infarct size nor the reduction of no-reflow with ischemic postconditioning was confirmed in a rabbit model,152 and no-reflow reduction by ischemic postconditioning was also not confirmed in pigs.153,154 In a mini-pig model of 3 hours of coronary occlusion/reperfusion, ischemic postconditioning with 6 cycles of 10-second reocclusion/10-second reperfusion reduced infarct size and area of no-reflow, but hypercholesterolemia abrogated the protection by ischemic postconditioning.155 In patients with reperfused acute myocardial infarction, ischemic postconditioning protocols reduced infarct size,47,156–164 improved coronary blood flow47,156,160,161,164 and coronary flow reserve,159 and reduced edema and no-reflow.163 However, neither the reduction of infarct size nor a reduction of microvascular obstruction was confirmed in other trials.165–170 Reasons for such discrepancy are not really clear but may relate to use of direct stenting or lack of it48,171 and the increasing use of P2Y12 antagonists which induce cardioprotection per se such that the potential for further protection is diminished.172–174

Coronary Vascular Protection by Remote Ischemic Conditioning

Remote ischemic conditioning was originally characterized as an interaction between two coronary vascular territories175 and has now been established as a powerful cardioprotective intervention which can be elicited from various vascular territories, including noninvasive occlusion/reperfusion of the limbs.176 Remote ischemic conditioning reduces infarct size when performed before (preconditioning), during (perconditioning), or after (postconditioning) sustained myocardial ischemia/reperfusion, and it has been confirmed in various species, including also proof-of-concept trials in humans undergoing elective interventional or surgical coronary revascularization or interventional/thrombolytic reperfusion of acute myocardial infarction. In pigs, remote ischemic preconditioning improved coronary blood flow through an ATP-dependent potassium channel–dependent mechanism.177 In healthy young volunteers, repeated remote ischemic conditioning twice a day for 1 week increased coronary flow reserve, and it did so also in patients with heart failure.178 In patients undergoing elective percutaneous coronary revascularization, remote ischemic preconditioning did not reduce coronary microvascular resistance in a nontarget vessel.179 In the Effect of Remote Ischemic Conditioning Before Hospital Admission (CONDI) trial, in patients undergoing primary PCI for acute myocardial infarction, remote ischemic perconditioning with 4 cycles of 5-minute arm ischemia/5-minute reperfusion during transport in the ambulance reduced infarct size but did not improve coronary blood flow.180 In patients with acute ST-segment elevation myocardial infarction undergoing PCI, remote ischemic perconditioning with 4 cycles of 5-minute arm ischemia/5-minute reperfusion at hospital admission reduced both infarct size and edema on MRI.181 Also in patients with acute myocardial infarction undergoing PCI, remote ischemic postconditioning by 3 cycles of lower limb ischemia/reperfusion reduced edema (MRI) and infarct size (MRI, biomarker), improved ST-segment resolution during reperfusion, but did not improve TIMI frame count or myocardial blush grading.182 In the recent LIPSIA (from Leipzig) conditioning trial in patients undergoing primary PCI for acute ST-segment elevation myocardial infarction, postconditioning alone with 4 cycles of 30-second reocclusion/reperfusion failed to improve myocardial salvage and microvascular obstruction by MRI, but combined postconditioning with remote ischemic perconditioning by 3 cycles of 5-minute upper arm ischemia/5-minute reperfusion improved myocardial salvage, albeit reduced microvascular obstruction only nonsignificantly.169 Myocardial salvage by remote ischemic preconditioning, in turn, is greater when collateral blood flow is present, as evident from a retrospective analysis of the CONDI trial and supporting the notion of a humoral transfer of cardioprotective factors from the remote organ to the heart.183 Remote ischemic preconditioning reduces leukocyte adhesion and phagocytosis in healthy volunteers,184 and it attenuates the increased platelet reactivity and formation of monocyte–platelet aggregates in patients undergoing ablation for atrial fibrillation185 and in patients undergoing coronary procedures.186 Remote ischemic preconditioning activates erythrocyte nitric oxide synthase187 and improves erythrocyte deformability,188 thus potentially antagonizing stasis.

Coronary Vascular Protection by Drugs and Cardioprotective Interventions

Experimental Studies

Most experimental studies on myocardial ischemia/reperfusion are performed in healthy and young animals which have a virgin coronary circulation without atherosclerosis, vascular remodeling, and endothelial dysfunction. Such studies accordingly cannot account for the presence of atherosclerosis with impaired endothelial function, exhaustion of autoregulatory mechanisms and coronary vascular remodelling distal to coronary stenoses,189 the development of a significant collateral circulation, and also pre-existing myocardial disease (patchy microinfarcts and fibrosis) or adaptation (hibernation). These limitations contribute to the difficulties in translating data from animal studies to the patient with acute myocardial infarction undergoing reperfusion therapy,8 apart from and in addition to confounding comorbidities and comedications.190

Drugs

As reviewed in detail elsewhere,35,191,192 many exogenous agents and drugs which often rely on the recruitment of signal transduction steps of conditioning maneuvers7 can reduce infarct size in various experimental models and in different species. In several such studies, the protection of the coronary circulation was also addressed. Adenosine, only when given at a high intracoronary dose for a prolonged period of time, reduced infarct size, no-reflow, and leukocyte infiltration in pigs.193 Also in pigs, cyclosporine A that inhibits opening of the mitochondrial permeability transition pore reduced not only infarct size when given just before reperfusion but also microvascular obstruction on MRI.194 Also, pretreatment with high-density lipoproteins from normocholesterolemic pigs which contain a load of sphingosine-1-phosphate195 reduced infarct size and the extent of no-reflow in pigs.196 Pretreatment with simvastatin reduced infarct size and the area of no-reflow in pigs, and such protection was related to activation of protein kinase A197 and of mitochondrial ATP-dependent potassium channels.198 Glucagon-like peptide 1 when given just before reperfusion in rats decreased infarct size and reduced the accumulation of leukocytes in the reperfused myocardium.199 Human recombinant angiopoietin-like peptide 4 reduced infarct size and area of no-reflow in mice and rabbits.69

Interventions

Hyperosmotic reperfusion with mannitol reduced edema and infarct size in pigs.200 Electric vagal nerve stimulation in pigs just before and into early reperfusion after 45-minute coronary occlusion reduced infarct size, area of no-reflow, and leukocyte accumulation, and the protective effects were related to nitric oxide synthase activity.201 Counterpulsation by an intra-aortic balloon pump during reperfusion after 60-minute coronary occlusion in pigs increased coronary blood flow and reduced infarct size and area of no-reflow.202 In contrast, partial clamping of the aorta to increase perfusion pressure augmented infarct size and no-reflow in pigs.203 Hypothermia (32°C) in rats and rabbits undergoing 30-minute coronary occlusion and reperfusion reduced infarct size and no-reflow area when initiated shortly after the onset of myocardial ischemia.204 Of note, whereas in rabbits undergoing 30-minute coronary occlusion with reperfusion, topical hypothermia (32°C) when initiated at 5 minutes before versus at 5 minutes after reperfusion tended to reduce infarct size only with hypothermia started before reperfusion, the area of no-reflow was reduced in both cases. When hypothermia was initiated no earlier than at 30-minute reperfusion, infarct size was not affected at all, but the area of no-reflow was still reduced. This particular study emphasizes the potential for a dissociation of effects on infarct size from those on area of no-reflow.205 Finally, cellular postconditioning by intracoronary infusion of allogeneic cardiosphere-derived cells in pigs at 30-minute reperfusion after 90-minute coronary occlusion reduced infarct size and area of microvascular obstruction 48 hours later.206

Clinical Studies

As reviewed in detail elsewhere,13,191,207 many different interventions and drugs have been used, after successful preclinical studies, as adjunct therapy to reperfusion with the aim to reduce infarct size and possibly improve clinical outcome. Most of these trials have failed to provide convincing evidence for infarct size reduction. Hypothermia did not reduce infarct size (single photon emission computed tomography) or improve TIMI flow in patients with acute myocardial infarction undergoing primary PCI.208 Also, no reduction of microvascular obstruction and infarct size was found with MRI.209–211 Hyperoxemia,212,213 aspiration or mechanical thrombectomy,214–221 and intra-aortic balloon counterpulsation222 did not reduce infarct size or improve coronary blood flow. More recently, also the cardioprotection by cyclosporine A which had been shown in a small-scale proof-of-concept trial223 was not confirmed in another smaller study with prethrombolytic cyclosporine A224 and, importantly, not in 2 larger-scale phase III trials, Does Cyclosporine Improve Clinical Outcome in ST Elevation Myocardial Infarction Patients (CIRCUS) and CyclosporinE A in Reperfused Myocardial Infarct (CYCLE).225,226 Many potential reasons for this discrepancy have been discussed, such as lack of direct stenting and greater use of P2Y12 antagonists, and also the use of a different vehicle in CIRCUS, but not in CYCLE.227

In some of these studies, not only infarct size but also parameters reflecting coronary microvascular function were reported, and the effects of cardioprotective drugs on infarct size and coronary microvascular function were mostly concordant (Figures 5–8). Intracoronary abciximab as compared with intravenous abciximab reduced infarct size (creatine kinase and MRI) and microvascular obstruction (MRI).228 For intracoronary adenosine, concordantly reduced infarct size (creatine kinase and MRI) and less microvascular obstruction (TIMI flow on angiography) were reported in patients undergoing interventional reperfusion for acute myocardial infarction in 2229,230 but not in 3 other studies.31,231,232 Intravenous nitrite in patients with ST-segment elevation myocardial infarction and interventional reperfusion failed to reduce infarct size (biomarker and MRI) or to affect TIMI flow (angiography).233 Intracoronary nitrite in patients with ST-segment elevation myocardial infarction and interventional reperfusion reduced infarct size (creatine kinase and MRI) only in a subgroup of patients with TIMI flow ≤1 at admission, and in this subgroup, intracoronary nitrite also reduced the area of microvascular obstruction (MRI).234 Erythropoietin in patients with ST-segment elevation myocardial infarction and interventional reperfusion neither reduced infarct size (creatine kinase and MRI) nor improved TIMI flow.235 Two different mitochondria-targeting drugs236,237 failed to reduce infarct size or to improve coronary microvascular function. Currently, only 4 drugs stand unchallenged to provide cardioprotection in term of infarct size reduction: atrial natriuretic peptide,238 metoprolol,32 esmolol,239 and exenatide,240–242 and no information on coronary microvascular function is available for these drugs.

Figure 5.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 5.

Forest plot of infarct size and thrombolysis in myocardial infarction (TIMI) flow grade in clinical trials reporting on both infarct size and microvascular dysfunction. The zero represents the mean value of the placebo group and gray bars the SEM of the placebo group. ■, mean values with significant difference from placebo; □, mean values without significant difference from placebo. Asp. Thromb indicates aspiration thrombectomy; CK, creatine kinase; CK-MB, creatine kinase muscle brain; hsTnT, high-sensitive troponin T; IABC, intra-aortic balloon counterpulsation; INT, intervention; MRI, magnetic resonance imaging; PLA, placebo; POCO, postconditioning; RIC, remote ischemic conditioning; SPECT, single photon emission computed tomography; and TnT, troponin T.

Figure 6.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 6.

Forest plot of infarct size and myocardial blush grade (MBG) in clinical trials reporting on both infarct size and microvascular dysfunction. The zero represents the mean value of the placebo group and gray bars the SEM of the placebo group. ■, mean values with significant difference from placebo; □, mean values without significant difference from placebo. Asp. Thromb. indicates aspiration thrombectomy; CK, creatine kinase; CK-MB, creatine kinase muscle brain; INT, intervention; Mech. Thromb., mechanical thrombectomy; MRI, magnetic resonance imaging; PLA, placebo; POCO, postconditioning; RIC, remote ischemic conditioning; SPECT, single photon emission computed tomography; and TnT, troponin T.

Figure 7.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 7.

Forest plot of infarct size and corrected thrombolysis in myocardial infarction frame count (cTFC) in clinical trials reporting on both infarct size and microvascular dysfunction. The zero represents the mean value of the placebo group and gray bars the SEM of the placebo group. ■, mean values with significant difference from placebo; □, mean values without significant difference from placebo. Asp. Thromb. indicates aspiration thrombectomy; CK-MB, creatine kinase muscle brain; INT, intervention; Mech. Thromb., mechanical thrombectomy; MRI, magnetic resonance imaging; PLA, placebo; POCO, postconditioning; RIC, remote ischemic conditioning; SPECT, single photon emission computed tomography; and TnT, troponin T.

Figure 8.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 8.

Forest plot of infarct size and edema and microvascular obstruction (MVO) on magnetic resonance imaging (MRI) in clinical trials reporting on both infarct size and microvascular dysfunction. The zero represents the mean value of the placebo group and gray bars the SEM of the placebo group. ■, mean values with significant difference from placebo; □, mean values without significant difference from placebo. Asp. Thromb. indicates aspiration thrombectomy; CK, creatine kinase; CK-MB, creatine kinase muscle brain; IABC, intra-aortic balloon counterpulsation; INT, intervention; PLA, placebo; POCO, postconditioning; RIC, remote ischemic conditioning; and TnI, troponin I.

Coronary Microvascular Injury: Cause or Consequence of Myocardial Ischemia/Reperfusion

The available studies indicate a close correlation between infarct size and that of no-reflow.243–245 Still, correlations cannot resolve questions of causality, and the lack of adequate techniques to make serial measurements of infarcted tissue and no-reflow with reasonable spatial resolution is largely responsible that causality between myocardial infarction and coronary microvascular no-reflow is not established.246 With microembolization of atherosclerotic debris, plugging of platelet/leukocyte aggregates and vasoconstriction in response to soluble mediators, the resulting coronary microvascular obstruction could be cause to myocardial infarction. With this rationale, thrombaspiration, protection devices, and coronary vasodilators are used to reduce peri-interventional reperfusion injury.101 Also, recombinant angiopoietin-like peptide 4 has been demonstrated to stabilize the endothelial barrier and subsequently reduce infarct size and no-reflow in mice.69 However, vice versa there may be primary damage to cardiomyocytes which only subsequently progresses to coronary microvascular damage, as seen in animal models with mechanical occlusion/reperfusion of virgin coronary arteries without a culprit lesion.247 Of particular interest to resolve a potential causality between infarct size and no-reflow are not the vast majority of studies where effects on both infarct size and no-reflow are concordant, but those few studies where they are dissociated. In pigs, edema at reperfusion after 48-minute coronary occlusion was reduced with both anoxic perfusion for catabolite washout during coronary occlusion and ischemic preconditioning by 2 cycles of 5-minute coronary occlusion/5-minute reperfusion, but only ischemic preconditioning also reduced infarct size.248 Delayed hypothermia starting no earlier than after 30-minute reperfusion following 30-minute coronary occlusion in rabbits reduced no-reflow, but not infarct size.205 In contrast, in a recent study in pigs with 60-minute coronary occlusion and reperfusion, ischemic postconditioning reduced infarct size, but not reflow.154 Although in most studies reduction of infarct size and no-reflow or lack thereof went in parallel, these studies with discordant effects on infarct size and no-reflow strongly argue against a strictly causal role for one in the other. In fact, there may rather be a common pathomechanism, such as damage by reactive oxygen species249 but with somewhat different, at least temporally different, impact on the myocardial and coronary microvascular compartment. Nothing is known on the signal transduction in endothelial and vascular smooth muscle cells which may confer protection from myocardial ischemia/reperfusion injury to the coronary circulation, and much research is needed here to help develop more effective and more specific therapeutic approaches to target coronary microvascular injury. It seems that mitochondrial dysfunction is central not only to myocardial ischemia/reperfusion injury but also to the impairment of metabolic coronary vasodilation, rendering it as a target to not only reduce infarct size but also improve coronary blood flow.250

Sources of Funding

G. Heusch was supported by the German Research Foundation (He 1320/18-3; SFB 1116/B8), the Hans and Gertie-Fischer Foundation, and the Heinz Horst-Deichmann Foundation.

Disclosures

None.

Footnotes

  • Nonstandard Abbreviations and Acronyms
    MRI
    magnetic resonance imaging
    PCI
    percutaneous coronary intervention
    TIMI
    thrombolysis in myocardial infarction

  • Received March 1, 2016.
  • Revision received March 17, 2016.
  • Accepted March 22, 2016.
  • © 2016 American Heart Association, Inc.

References

  1. 1.↵
    1. Heusch G,
    2. Schulz R.
    Neglect of the coronary circulation: some critical remarks on problems in the translation of cardioprotection. Cardiovasc Res. 2009;84:11–14. doi: 10.1093/cvr/cvp210.
    OpenUrlFREE Full Text
  2. 2.↵
    1. Heusch G,
    2. Kleinbongard P,
    3. Skyschally A,
    4. Levkau B,
    5. Schulz R,
    6. Erbel R.
    The coronary circulation in cardioprotection: more than just one confounder. Cardiovasc Res. 2012;94:237–245. doi: 10.1093/cvr/cvr271.
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    1. Thygesen K,
    2. Alpert JS,
    3. Jaffe AS,
    4. et al.,
    5. Writing Group on the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction; ESC Committee for Practice Guidelines (CPG)
    . Third universal definition of myocardial infarction. Eur Heart J. 2012;33:2551–2567. doi: 10.1093/eurheartj/ehs184.
    OpenUrlFREE Full Text
  4. 4.↵
    1. Heusch G.
    Postconditioning: old wine in a new bottle? J Am Coll Cardiol. 2004;44:1111–1112. doi: 10.1016/j.jacc.2004.06.013.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Yellon DM,
    2. Hausenloy DJ.
    Myocardial reperfusion injury. N Engl J Med. 2007;357:1121–1135. doi: 10.1056/NEJMra071667.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Hausenloy DJ,
    2. Yellon DM.
    Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest. 2013;123:92–100. doi: 10.1172/JCI62874.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Heusch G.
    Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res. 2015;116:674–699. doi: 10.1161/CIRCRESAHA.116.305348.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Heusch G.
    Cardioprotection: chances and challenges of its translation to the clinic. Lancet. 2013;381:166–175. doi: 10.1016/S0140-6736(12)60916-7.
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Mehta LS,
    2. Beckie TM,
    3. DeVon HA,
    4. Grines CL,
    5. Krumholz HM,
    6. Johnson MN,
    7. Lindley KJ,
    8. Vaccarino V,
    9. Wang TY,
    10. Watson KE,
    11. Wenger NK,
    12. American Heart Association Cardiovascular Disease in Women and Special Populations Committee of the Council on Clinical Cardiology, Council on Epidemiology and Prevention, Council on Cardiovascular and Stroke Nursing, and Council on Quality of Care and Outcomes Research
    . Acute myocardial infarction in women: a scientific statement from the American Heart Association. Circulation. 2016;133:916–947. doi: 10.1161/CIR.0000000000000351.
    OpenUrlAbstract/FREE Full Text
  10. 10.↵
    1. Sack MN,
    2. Murphy E.
    The role of comorbidities in cardioprotection. J Cardiovasc Pharmacol Ther. 2011;16:267–272. doi: 10.1177/1074248411408313.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. Pepine CJ,
    2. Ferdinand KC,
    3. Shaw LJ,
    4. Light-McGroary KA,
    5. Shah RU,
    6. Gulati M,
    7. Duvernoy C,
    8. Walsh MN,
    9. Bairey Merz CN,
    10. ACC CVD in Women Committee
    . Emergence of nonobstructive coronary artery disease: a woman’s problem and need for change in definition on angiography. J Am Coll Cardiol. 2015;66:1918–1933. doi: 10.1016/j.jacc.2015.08.876.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Skyschally A,
    2. Schulz R,
    3. Heusch G.
    Pathophysiology of myocardial infarction: protection by ischemic pre- and postconditioning. Herz. 2008;33:88–100. doi: 10.1007/s00059-008-3101-9.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Ibáñez B,
    2. Heusch G,
    3. Ovize M,
    4. Van de Werf F.
    Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol. 2015;65:1454–1471. doi: 10.1016/j.jacc.2015.02.032.
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Heyndrickx GR,
    2. Millard RW,
    3. McRitchie RJ,
    4. Maroko PR,
    5. Vatner SF.
    Regional myocardial functional and electrophysiological alterations after brief coronary artery occlusion in conscious dogs. J Clin Invest. 1975;56:978–985. doi: 10.1172/JCI108178.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Braunwald E,
    2. Kloner RA.
    The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation. 1982;66:1146–1149.
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Bolli R.
    Mechanism of myocardial “stunning”. Circulation. 1990;82:723–738.
    OpenUrlAbstract/FREE Full Text
  17. 17.↵
    1. Bolli R,
    2. Marbán E.
    Molecular and cellular mechanisms of myocardial stunning. Physiol Rev. 1999;79:609–634.
    OpenUrlAbstract/FREE Full Text
  18. 18.↵
    1. Heusch G.
    Hibernating myocardium. Physiol Rev. 1998;78:1055–1085.
    OpenUrlAbstract/FREE Full Text
  19. 19.↵
    1. Heusch G,
    2. Schulz R,
    3. Rahimtoola SH.
    Myocardial hibernation: a delicate balance. Am J Physiol Heart Circ Physiol. 2005;288:H984–H999. doi: 10.1152/ajpheart.01109.2004.
    OpenUrlAbstract/FREE Full Text
  20. 20.↵
    1. Reimer KA,
    2. Lowe JE,
    3. Rasmussen MM,
    4. Jennings RB.
    The wavefront phenomenon of ischemic cell death. 1. Myocardial infarct size vs duration of coronary occlusion in dogs. Circulation. 1977;56:786–794.
    OpenUrlAbstract/FREE Full Text
  21. 21.↵
    1. Reimer KA,
    2. Jennings RB.
    The “wavefront phenomenon” of myocardial ischemic cell death. II. Transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and collateral flow. Lab Invest. 1979;40:633–644.
    OpenUrlPubMed
  22. 22.↵
    1. Schaper W,
    2. Görge G,
    3. Winkler B,
    4. Schaper J.
    The collateral circulation of the heart. Prog Cardiovasc Dis. 1988;31:57–77.
    OpenUrlCrossRefPubMed
  23. 23.↵
    1. Horneffer PJ,
    2. Healy B,
    3. Gott VL,
    4. Gardner TJ.
    The rapid evolution of a myocardial infarction in an end-artery coronary preparation. Circulation. 1987;76:V39–V42.
    OpenUrlPubMed
  24. 24.↵
    1. Pich S,
    2. Klein HH,
    3. Lindert S,
    4. Nebendahl K,
    5. Kreuzer H.
    Cell death in ischemic, reperfused porcine hearts: a histochemical and functional study. Basic Res Cardiol. 1988;83:550–559.
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Yang XM,
    2. Liu Y,
    3. Liu Y,
    4. Tandon N,
    5. Kambayashi J,
    6. Downey JM,
    7. Cohen MV.
    Attenuation of infarction in cynomolgus monkeys: preconditioning and postconditioning. Basic Res Cardiol. 2010;105:119–128. doi: 10.1007/s00395-009-0050-2.
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Cinca J,
    2. Carreño A,
    3. Mont L,
    4. Blanch P,
    5. Soler-Soler J.
    Neurally mediated negative inotropic effect impairs myocardial function during cholinergic coronary vasoconstriction in pigs. Circulation. 1996;94:1101–1108.
    OpenUrlAbstract/FREE Full Text
  27. 27.↵
    1. Oudiz R,
    2. Heusch G,
    3. Guth BD.
    Selective alpha1- and alpha2- adrenergic coronary vasoconstriction in anesthetized swine. Faseb J. 1989;3:A896-(abstr.).
    OpenUrl
  28. 28.↵
    1. Heusch G,
    2. Baumgart D,
    3. Camici P,
    4. Chilian W,
    5. Gregorini L,
    6. Hess O,
    7. Indolfi C,
    8. Rimoldi O.
    Alpha-adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circulation. 2000;101:689–694.
    OpenUrlAbstract/FREE Full Text
  29. 29.↵
    1. Ludmer PL,
    2. Selwyn AP,
    3. Shook TL,
    4. Wayne RR,
    5. Mudge GH,
    6. Alexander RW,
    7. Ganz P.
    Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986;315:1046–1051. doi: 10.1056/NEJM198610233151702.
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Hedström E,
    2. Engblom H,
    3. Frogner F,
    4. Aström-Olsson K,
    5. Ohlin H,
    6. Jovinge S,
    7. Arheden H.
    Infarct evolution in man studied in patients with first-time coronary occlusion in comparison to different species - implications for assessment of myocardial salvage. J Cardiovasc Magn Reson. 2009;11:38. doi: 10.1186/1532-429X-11-38.
    OpenUrlCrossRefPubMed
  31. 31.↵
    1. Desmet W,
    2. Bogaert J,
    3. Dubois C,
    4. Sinnaeve P,
    5. Adriaenssens T,
    6. Pappas C,
    7. Ganame J,
    8. Dymarkowski S,
    9. Janssens S,
    10. Belmans A,
    11. Van de Werf F.
    High-dose intracoronary adenosine for myocardial salvage in patients with acute ST-segment elevation myocardial infarction. Eur Heart J. 2011;32:867–877. doi: 10.1093/eurheartj/ehq492.
    OpenUrlAbstract/FREE Full Text
  32. 32.↵
    1. Ibanez B,
    2. Macaya C,
    3. Sánchez-Brunete V,
    4. et al
    . Effect of early metoprolol on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial. Circulation. 2013;128:1495–1503. doi: 10.1161/CIRCULATIONAHA.113.003653.
    OpenUrlAbstract/FREE Full Text
  33. 33.↵
    1. Schömig A,
    2. Mehilli J,
    3. Antoniucci D,
    4. et al.,
    5. Beyond 12 hours Reperfusion AlternatiVe Evaluation (BRAVE-2) Trial Investigators
    . Mechanical reperfusion in patients with acute myocardial infarction presenting more than 12 hours from symptom onset: a randomized controlled trial. JAMA. 2005;293:2865–2872. doi: 10.1001/jama.293.23.2865.
    OpenUrlCrossRefPubMed
  34. 34.↵
    1. Ndrepepa G,
    2. Kastrati A,
    3. Mehilli J,
    4. Antoniucci D,
    5. Schömig A.
    Mechanical reperfusion and long-term mortality in patients with acute myocardial infarction presenting 12 to 48 hours from onset of symptoms. JAMA. 2009;301:487–488. doi: 10.1001/jama.2009.32.
    OpenUrlCrossRefPubMed
  35. 35.↵
    1. Kleinbongard P,
    2. Heusch G.
    Extracellular signalling molecules in the ischaemic/reperfused heart - druggable and translatable for cardioprotection? Br J Pharmacol. 2015;172:2010–2025. doi: 10.1111/bph.12902.
    OpenUrlCrossRefPubMed
  36. 36.↵
    1. Heusch G.
    Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: benefit from selective bradycardic agents. Br J Pharmacol. 2008;153:1589–1601. doi: 10.1038/sj.bjp.0707673.
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Murry CE,
    2. Jennings RB,
    3. Reimer KA.
    Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124–1136.
    OpenUrlAbstract/FREE Full Text
  38. 38.↵
    1. Zhao ZQ,
    2. Corvera JS,
    3. Halkos ME,
    4. Kerendi F,
    5. Wang NP,
    6. Guyton RA,
    7. Vinten-Johansen J.
    Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2003;285:H579–H588. doi: 10.1152/ajpheart.01064.2002.
    OpenUrlAbstract/FREE Full Text
  39. 39.↵
    1. Maroko PR,
    2. Libby P,
    3. Ginks WR,
    4. Bloor CM,
    5. Shell WE,
    6. Sobel BE,
    7. Ross J Jr.
    . Coronary artery reperfusion. I. Early effects on local myocardial function and the extent of myocardial necrosis. J Clin Invest. 1972;51:2710–2716. doi: 10.1172/JCI107090.
    OpenUrlCrossRefPubMed
  40. 40.↵
    1. Ginks WR,
    2. Sybers HD,
    3. Maroko PR,
    4. Covell JW,
    5. Sobel BE,
    6. Ross J Jr.
    . Coronary artery reperfusion. II. Reduction of myocardial infarct size at 1 week after the coronary occlusion. J Clin Invest. 1972;51:2717–2723. doi: 10.1172/JCI107091.
    OpenUrlCrossRefPubMed
  41. 41.↵
    1. Hartzler GO,
    2. Rutherford BD,
    3. McConahay DR,
    4. Johnson WL Jr.,
    5. McCallister BD,
    6. Gura GM Jr.,
    7. Conn RC,
    8. Crockett JE.
    Percutaneous transluminal coronary angioplasty with and without thrombolytic therapy for treatment of acute myocardial infarction. Am Heart J. 1983;106:965–973.
    OpenUrlCrossRefPubMed
  42. 42.↵
    Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). Lancet. 1986;1:397–402.
    OpenUrlCrossRefPubMed
  43. 43.↵
    Randomised trial of intravenous atenolol among 16 027 cases of suspected acute mycardial infarction: ISIS-1. Lancet. 1986;2:57–69.
    OpenUrlCrossRefPubMed
  44. 44.↵
    1. Krug A,
    2. Du Mesnil de Rochemont,
    3. Korb G.
    Blood supply of the myocardium after temporary coronary occlusion. Circ Res. 1966;19:57–62.
    OpenUrlAbstract/FREE Full Text
  45. 45.↵
    1. Kloner RA,
    2. Ganote CE,
    3. Jennings RB.
    The “no-reflow” phenomenon after temporary coronary occlusion in the dog. J Clin Invest. 1974;54:1496–1508. doi: 10.1172/JCI107898.
    OpenUrlCrossRefPubMed
  46. 46.↵
    1. Przyklenk K.
    Lethal myocardial “reperfusion injury”: The opinions of good men. J Thromb Thrombolysis. 1997;4:5–6.
    OpenUrlCrossRefPubMed
  47. 47.↵
    1. Staat P,
    2. Rioufol G,
    3. Piot C,
    4. Cottin Y,
    5. Cung TT,
    6. L’Huillier I,
    7. Aupetit JF,
    8. Bonnefoy E,
    9. Finet G,
    10. André-Fouët X,
    11. Ovize M.
    Postconditioning the human heart. Circulation. 2005;112:2143–2148. doi: 10.1161/CIRCULATIONAHA.105.558122.
    OpenUrlAbstract/FREE Full Text
  48. 48.↵
    1. Heusch G.
    Reduction of infarct size by ischaemic post-conditioning in humans: fact or fiction? Eur Heart J. 2012;33:13–15. doi: 10.1093/eurheartj/ehr341.
    OpenUrlFREE Full Text
  49. 49.↵
    1. Okamoto F,
    2. Allen BS,
    3. Buckberg GD,
    4. Bugyi H,
    5. Leaf J.
    Reperfusion conditions: importance of ensuring gentle versus sudden reperfusion during relief of coronary occlusion. J Thorac Cardiovasc Surg. 1986;92:613–620.
    OpenUrlPubMed
  50. 50.↵
    1. Ferrera R,
    2. Benhabbouche S,
    3. Da Silva CC,
    4. Alam MR,
    5. Ovize M.
    Delayed low pressure at reperfusion: a new approach for cardioprotection. J Thorac Cardiovasc Surg. 2015;150:1641–8.e2. doi: 10.1016/j.jtcvs.2015.08.053.
    OpenUrlCrossRefPubMed
  51. 51.↵
    1. Musiolik J,
    2. van Caster P,
    3. Skyschally A,
    4. Boengler K,
    5. Gres P,
    6. Schulz R,
    7. Heusch G.
    Reduction of infarct size by gentle reperfusion without activation of reperfusion injury salvage kinases in pigs. Cardiovasc Res. 2010;85:110–117. doi: 10.1093/cvr/cvp271.
    OpenUrlAbstract/FREE Full Text
  52. 52.↵
    1. Heusch G.
    Treatment of myocardial ischemia/reperfusion injury by ischemic and pharmacological postconditioning. Compr Physiol. 2015;5:1123–1145. doi: 10.1002/cphy.c140075.
    OpenUrlPubMed
  53. 53.↵
    1. Schaper W,
    2. Frenzel H,
    3. Hort W.
    Experimental coronary artery occlusion. I. Measurement of infarct size. Basic Res Cardiol. 1979;74:46–53.
    OpenUrlCrossRefPubMed
  54. 54.↵
    1. Fishbein MC,
    2. Meerbaum S,
    3. Rit J,
    4. Lando U,
    5. Kanmatsuse K,
    6. Mercier JC,
    7. Corday E,
    8. Ganz W.
    Early phase acute myocardial infarct size quantification: validation of the triphenyl tetrazolium chloride tissue enzyme staining technique. Am Heart J. 1981;101:593–600.
    OpenUrlCrossRefPubMed
  55. 55.↵
    1. Kloner RA.
    No-reflow phenomenon: maintaining vascular integrity. J Cardiovasc Pharmacol Ther. 2011;16:244–250. doi: 10.1177/1074248411405990.
    OpenUrlAbstract/FREE Full Text
  56. 56.↵
    1. Sheehan FH,
    2. Braunwald E,
    3. Canner P,
    4. Dodge HT,
    5. Gore J,
    6. Van Natta P,
    7. Passamani ER,
    8. Williams DO,
    9. Zaret B.
    The effect of intravenous thrombolytic therapy on left ventricular function: a report on tissue-type plasminogen activator and streptokinase from the Thrombolysis in Myocardial Infarction (TIMI Phase I) trial. Circulation. 1987;75:817–829.
    OpenUrlAbstract/FREE Full Text
  57. 57.↵
    1. Gibson CM,
    2. Cannon CP,
    3. Daley WL,
    4. Dodge JT Jr.,
    5. Alexander B Jr.,
    6. Marble SJ,
    7. McCabe CH,
    8. Raymond L,
    9. Fortin T,
    10. Poole WK,
    11. Braunwald E.
    TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation. 1996;93:879–888.
    OpenUrlAbstract/FREE Full Text
  58. 58.↵
    1. van ‘t Hof AW,
    2. Liem A,
    3. Suryapranata H,
    4. Hoorntje JC,
    5. de Boer MJ,
    6. Zijlstra F.
    Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade. Zwolle Myocardial Infarction Study Group. Circulation. 1998;97:2302–2306.
    OpenUrlAbstract/FREE Full Text
  59. 59.↵
    1. Niccoli G,
    2. Burzotta F,
    3. Galiuto L,
    4. Crea F.
    Myocardial no-reflow in humans. J Am Coll Cardiol. 2009;54:281–292. doi: 10.1016/j.jacc.2009.03.054.
    OpenUrlCrossRefPubMed
  60. 60.↵
    1. Dauber IM,
    2. VanBenthuysen KM,
    3. McMurtry IF,
    4. Wheeler GS,
    5. Lesnefsky EJ,
    6. Horwitz LD,
    7. Weil JV.
    Functional coronary microvascular injury evident as increased permeability due to brief ischemia and reperfusion. Circ Res. 1990;66:986–998.
    OpenUrlAbstract/FREE Full Text
  61. 61.↵
    1. García-Dorado D,
    2. Oliveras J,
    3. Gili J,
    4. Sanz E,
    5. Pérez-Villa F,
    6. Barrabés J,
    7. Carreras MJ,
    8. Solares J,
    9. Soler-Soler J.
    Analysis of myocardial oedema by magnetic resonance imaging early after coronary artery occlusion with or without reperfusion. Cardiovasc Res. 1993;27:1462–1469.
    OpenUrlAbstract/FREE Full Text
  62. 62.↵
    1. Garcia-Dorado D,
    2. Oliveras J.
    Myocardial oedema: a preventable cause of reperfusion injury? Cardiovasc Res. 1993;27:1555–1563.
    OpenUrlFREE Full Text
  63. 63.↵
    1. Abdel-Aty H,
    2. Cocker M,
    3. Meek C,
    4. Tyberg JV,
    5. Friedrich MG.
    Edema as a very early marker for acute myocardial ischemia: a cardiovascular magnetic resonance study. J Am Coll Cardiol. 2009;53:1194–1201. doi: 10.1016/j.jacc.2008.10.065.
    OpenUrlCrossRefPubMed
  64. 64.↵
    1. Garcia-Dorado D,
    2. Andres-Villarreal M,
    3. Ruiz-Meana M,
    4. Inserte J,
    5. Barba I.
    Myocardial edema: a translational view. J Mol Cell Cardiol. 2012;52:931–939. doi: 10.1016/j.yjmcc.2012.01.010.
    OpenUrlCrossRefPubMed
  65. 65.↵
    1. Noll T,
    2. Muhs A,
    3. Besselmann M,
    4. Watanabe H,
    5. Piper HM.
    Initiation of hyperpermeability in energy-depleted coronary endothelial monolayers. Am J Physiol. 1995;268:H1462–H1470.
    OpenUrl
  66. 66.↵
    1. Becker BF,
    2. Chappell D,
    3. Jacob M.
    Endothelial glycocalyx and coronary vascular permeability: the fringe benefit. Basic Res Cardiol. 2010;105:687–701. doi: 10.1007/s00395-010-0118-z.
    OpenUrlCrossRefPubMed
  67. 67.↵
    1. Juchem G,
    2. Weiss DR,
    3. Knott M,
    4. Senftl A,
    5. Förch S,
    6. Fischlein T,
    7. Kreuzer E,
    8. Reichart B,
    9. Laufer S,
    10. Nees S.
    Regulation of coronary venular barrier function by blood borne inflammatory mediators and pharmacological tools: insights from novel microvascular wall models. Am J Physiol Heart Circ Physiol. 2012;302:H567–H581. doi: 10.1152/ajpheart.00360.2011.
    OpenUrlAbstract/FREE Full Text
  68. 68.↵
    1. Kuhne W,
    2. Besselmann M,
    3. Noll T,
    4. Muhs A,
    5. Watanabe H,
    6. Piper HM.
    Disintegration of cytoskeletal structure of actin filaments in energy-depleted endothelial cells. Am J Physiol. 1993;264:H1599–H1608.
    OpenUrl
  69. 69.↵
    1. Galaup A,
    2. Gomez E,
    3. Souktani R,
    4. et al
    . Protection against myocardial infarction and no-reflow through preservation of vascular integrity by angiopoietin-like 4. Circulation. 2012;125:140–149. doi: 10.1161/CIRCULATIONAHA.111.049072.
    OpenUrlAbstract/FREE Full Text
  70. 70.↵
    1. Li Z,
    2. Jin ZQ.
    Ischemic preconditioning enhances integrity of coronary endothelial tight junctions. Biochem Biophys Res Commun. 2012;425:630–635. doi: 10.1016/j.bbrc.2012.07.130.
    OpenUrlCrossRefPubMed
  71. 71.↵
    1. Aslam M,
    2. Schluter KD,
    3. Rohrbach S,
    4. Rafiq A,
    5. Nazli S,
    6. Piper HM,
    7. Noll T,
    8. Schulz R,
    9. Gündüz D.
    Hypoxia-reoxygenation-induced endothelial barrier failure: role of RhoA, Rac1 and myosin light chain kinase. J Physiol. 2013;591:461–473. doi: 10.1113/jphysiol.2012.237834.
    OpenUrlCrossRefPubMed
  72. 72.↵
    1. Gündüz D,
    2. Aslam M,
    3. Krieger U,
    4. Becker L,
    5. Grebe M,
    6. Arshad M,
    7. Sedding DG,
    8. Härtel FV,
    9. Abdallah Y,
    10. Piper HM,
    11. Voss RK,
    12. Noll T.
    Opposing effects of ATP and adenosine on barrier function of rat coronary microvasculature. J Mol Cell Cardiol. 2012;52:962–970. doi: 10.1016/j.yjmcc.2012.01.003.
    OpenUrlCrossRefPubMed
  73. 73.↵
    1. van den Berg BM,
    2. Vink H,
    3. Spaan JA.
    The endothelial glycocalyx protects against myocardial edema. Circ Res. 2003;92:592–594. doi: 10.1161/01.RES.0000065917.53950.75.
    OpenUrlAbstract/FREE Full Text
  74. 74.↵
    1. Annecke T,
    2. Fischer J,
    3. Hartmann H,
    4. Tschoep J,
    5. Rehm M,
    6. Conzen P,
    7. Sommerhoff CP,
    8. Becker BF.
    Shedding of the coronary endothelial glycocalyx: effects of hypoxia/reoxygenation vs ischaemia/reperfusion. Br J Anaesth. 2011;107:679–686. doi: 10.1093/bja/aer269.
    OpenUrlAbstract/FREE Full Text
  75. 75.↵
    1. Chappell D,
    2. Hofmann-Kiefer K,
    3. Jacob M,
    4. Rehm M,
    5. Briegel J,
    6. Welsch U,
    7. Conzen P,
    8. Becker BF.
    TNF-alpha induced shedding of the endothelial glycocalyx is prevented by hydrocortisone and antithrombin. Basic Res Cardiol. 2009;104:78–89. doi: 10.1007/s00395-008-0749-5.
    OpenUrlCrossRefPubMed
  76. 76.↵
    1. Chappell D,
    2. Dörfler N,
    3. Jacob M,
    4. Rehm M,
    5. Welsch U,
    6. Conzen P,
    7. Becker BF.
    Glycocalyx protection reduces leukocyte adhesion after ischemia/reperfusion. Shock. 2010;34:133–139. doi: 10.1097/SHK.0b013e3181cdc363.
    OpenUrlCrossRefPubMed
  77. 77.↵
    1. Chappell D,
    2. Brettner F,
    3. Doerfler N,
    4. Jacob M,
    5. Rehm M,
    6. Bruegger D,
    7. Conzen P,
    8. Jacob B,
    9. Becker BF.
    Protection of glycocalyx decreases platelet adhesion after ischaemia/reperfusion: an animal study. Eur J Anaesthesiol. 2014;31:474–481. doi: 10.1097/EJA.0000000000000085.
    OpenUrlCrossRefPubMed
  78. 78.↵
    1. Bruegger D,
    2. Rehm M,
    3. Jacob M,
    4. Chappell D,
    5. Stoeckelhuber M,
    6. Welsch U,
    7. Conzen P,
    8. Becker BF.
    Exogenous nitric oxide requires an endothelial glycocalyx to prevent postischemic coronary vascular leak in guinea pig hearts. Crit Care. 2008;12:R73. doi: 10.1186/cc6913.
    OpenUrlCrossRefPubMed
  79. 79.↵
    1. Fernández-Jiménez R,
    2. García-Prieto J,
    3. Sánchez-González J,
    4. Agüero J,
    5. López-Martín GJ,
    6. Galán-Arriola C,
    7. Molina-Iracheta A,
    8. Doohan R,
    9. Fuster V,
    10. Ibáñez B.
    Pathophysiology underlying the bimodal edema phenomenon after myocardial ischemia/reperfusion. J Am Coll Cardiol. 2015;66:816–828. doi: 10.1016/j.jacc.2015.06.023.
    OpenUrlCrossRefPubMed
  80. 80.↵
    1. Aletras AH,
    2. Tilak GS,
    3. Natanzon A,
    4. Hsu LY,
    5. Gonzalez FM,
    6. Hoyt RF Jr.,
    7. Arai AE.
    Retrospective determination of the area at risk for reperfused acute myocardial infarction with T2-weighted cardiac magnetic resonance imaging: histopathological and displacement encoding with stimulated echoes (DENSE) functional validations. Circulation. 2006;113:1865–1870. doi: 10.1161/CIRCULATIONAHA.105.576025.
    OpenUrlAbstract/FREE Full Text
  81. 81.↵
    1. Mewton N,
    2. Rapacchi S,
    3. Augeul L,
    4. Ferrera R,
    5. Loufouat J,
    6. Boussel L,
    7. Micolich A,
    8. Rioufol G,
    9. Revel D,
    10. Ovize M,
    11. Croisille P.
    Determination of the myocardial area at risk with pre- versus post-reperfusion imaging techniques in the pig model. Basic Res Cardiol. 2011;106:1247–1257. doi: 10.1007/s00395-011-0214-8.
    OpenUrlCrossRefPubMed
  82. 82.↵
    1. Heusch P,
    2. Nensa F,
    3. Heusch G.
    Is MRI really the gold standard for the quantification of salvage from myocardial infarction? Circ Res. 2015;117:222–224. doi: 10.1161/CIRCRESAHA.117.306929.
    OpenUrlFREE Full Text
  83. 83.↵
    1. Frame LH,
    2. Powell WJ Jr.
    . Progressive perfusion impairment during prolonged low flow myocardial ischemia in dogs. Circ Res. 1976;39:269–276.
    OpenUrlAbstract/FREE Full Text
  84. 84.↵
    1. Manciet LH,
    2. Poole DC,
    3. McDonagh PF,
    4. Copeland JG,
    5. Mathieu-Costello O.
    Microvascular compression during myocardial ischemia: mechanistic basis for no-reflow phenomenon. Am J Physiol. 1994;266:H1541–H1550.
    OpenUrl
  85. 85.↵
    1. Aversano T,
    2. Becker LC.
    Persistence of coronary vasodilator reserve despite functionally significant flow reduction. Am J Physiol. 1985;248:H403–H411.
    OpenUrl
  86. 86.↵
    1. Canty JM Jr.,
    2. Klocke FJ.
    Reduced regional myocardial perfusion in the presence of pharmacologic vasodilator reserve. Circulation. 1985;71:370–377.
    OpenUrlAbstract/FREE Full Text
  87. 87.↵
    1. Gross GJ,
    2. O’Rourke ST,
    3. Pelc LR,
    4. Warltier DC.
    Myocardial and endothelial dysfunction after multiple, brief coronary occlusions: role of oxygen radicals. Am J Physiol. 1992;263:H1703–H1709.
    OpenUrl
  88. 88.↵
    1. Ehring T,
    2. Krajcar M,
    3. Baumgart D,
    4. Kompa S,
    5. Hümmelgen M,
    6. Heusch G.
    Cholinergic and alpha-adrenergic coronary vasomotion [corrected] with increasing ischemia-reperfusion injury. Am J Physiol. 1995;268:H886–H894.
    OpenUrl
  89. 89.↵
    1. Heusch G,
    2. Deussen A.
    The effects of cardiac sympathetic nerve stimulation on perfusion of stenotic coronary arteries in the dog. Circ Res. 1983;53:8–15.
    OpenUrlFREE Full Text
  90. 90.↵
    1. Heusch G,
    2. Deussen A,
    3. Thämer V.
    Cardiac sympathetic nerve activity and progressive vasoconstriction distal to coronary stenoses: feed-back aggravation of myocardial ischemia. J Auton Nerv Syst. 1985;13:311–326.
    OpenUrlCrossRefPubMed
  91. 91.↵
    1. Baumgart D,
    2. Haude M,
    3. Görge G,
    4. Liu F,
    5. Ge J,
    6. Grosse-Eggebrecht C,
    7. Erbel R,
    8. Heusch G.
    Augmented alpha-adrenergic constriction of atherosclerotic human coronary arteries. Circulation. 1999;99:2090–2097.
    OpenUrlAbstract/FREE Full Text
  92. 92.↵
    1. Gregorini L,
    2. Marco J,
    3. Kozàkovà M,
    4. Palombo C,
    5. Anguissola GB,
    6. Marco I,
    7. Bernies M,
    8. Cassagneau B,
    9. Distante A,
    10. Bossi IM,
    11. Fajadet J,
    12. Heusch G.
    Alpha-adrenergic blockade improves recovery of myocardial perfusion and function after coronary stenting in patients with acute myocardial infarction. Circulation. 1999;99:482–490.
    OpenUrlAbstract/FREE Full Text
  93. 93.↵
    1. Gregorini L,
    2. Marco J,
    3. Farah B,
    4. Bernies M,
    5. Palombo C,
    6. Kozàkovà M,
    7. Bossi IM,
    8. Cassagneau B,
    9. Fajadet J,
    10. Di Mario C,
    11. Albiero R,
    12. Cugno M,
    13. Grossi A,
    14. Heusch G.
    Effects of selective alpha1- and alpha2-adrenergic blockade on coronary flow reserve after coronary stenting. Circulation. 2002;106:2901–2907.
    OpenUrlAbstract/FREE Full Text
  94. 94.↵
    1. Leineweber K,
    2. Böse D,
    3. Vogelsang M,
    4. Haude M,
    5. Erbel R,
    6. Heusch G.
    Intense vasoconstriction in response to aspirate from stented saphenous vein aortocoronary bypass grafts. J Am Coll Cardiol. 2006;47:981–986. doi: 10.1016/j.jacc.2005.10.053.
    OpenUrlCrossRefPubMed
  95. 95.↵
    1. Kleinbongard P,
    2. Böse D,
    3. Baars T,
    4. Möhlenkamp S,
    5. Konorza T,
    6. Schöner S,
    7. Elter-Schulz M,
    8. Eggebrecht H,
    9. Degen H,
    10. Haude M,
    11. Levkau B,
    12. Schulz R,
    13. Erbel R,
    14. Heusch G.
    Vasoconstrictor potential of coronary aspirate from patients undergoing stenting of saphenous vein aortocoronary bypass grafts and its pharmacological attenuation. Circ Res. 2011;108:344–352. doi: 10.1161/CIRCRESAHA.110.235713.
    OpenUrlAbstract/FREE Full Text
  96. 96.↵
    1. Kleinbongard P,
    2. Baars T,
    3. Möhlenkamp S,
    4. Kahlert P,
    5. Erbel R,
    6. Heusch G.
    Aspirate from human stented native coronary arteries vs. saphenous vein grafts: more endothelin but less particulate debris. Am J Physiol Heart Circ Physiol. 2013;305:H1222–H1229. doi: 10.1152/ajpheart.00358.2013.
    OpenUrlAbstract/FREE Full Text
  97. 97.↵
    1. Ku DD.
    Coronary vascular reactivity after acute myocardial ischemia. Science. 1982;218:576–578.
    OpenUrlAbstract/FREE Full Text
  98. 98.↵
    1. Bolli R,
    2. Triana JF,
    3. Jeroudi MO.
    Prolonged impairment of coronary vasodilation after reversible ischemia. Evidence for microvascular “stunning”. Circ Res. 1990;67:332–343.
    OpenUrlAbstract/FREE Full Text
  99. 99.↵
    1. Mills I,
    2. Fallon JT,
    3. Wrenn D,
    4. Sasken H,
    5. Gray W,
    6. Bier J,
    7. Levine D,
    8. Berman S,
    9. Gilson M,
    10. Gewirtz H.
    Adaptive responses of coronary circulation and myocardium to chronic reduction in perfusion pressure and flow. Am J Physiol. 1994;266:H447–H457.
    OpenUrl
  100. 100.↵
    1. Sorop O,
    2. Merkus D,
    3. de Beer VJ,
    4. Houweling B,
    5. Pistea A,
    6. McFalls EO,
    7. Boomsma F,
    8. van Beusekom HM,
    9. van der Giessen WJ,
    10. VanBavel E,
    11. Duncker DJ.
    Functional and structural adaptations of coronary microvessels distal to a chronic coronary artery stenosis. Circ Res. 2008;102:795–803. doi: 10.1161/CIRCRESAHA.108.172528.
    OpenUrlAbstract/FREE Full Text
  101. 101.↵
    1. Heusch G,
    2. Kleinbongard P,
    3. Böse D,
    4. Levkau B,
    5. Haude M,
    6. Schulz R,
    7. Erbel R.
    Coronary microembolization: from bedside to bench and back to bedside. Circulation. 2009;120:1822–1836. doi: 10.1161/CIRCULATIONAHA.109.888784.
    OpenUrlAbstract/FREE Full Text
  102. 102.↵
    1. Dörge H,
    2. Neumann T,
    3. Behrends M,
    4. Skyschally A,
    5. Schulz R,
    6. Kasper C,
    7. Erbel R,
    8. Heusch G.
    Perfusion-contraction mismatch with coronary microvascular obstruction: role of inflammation. Am J Physiol Heart Circ Physiol. 2000;279:H2587–H2592.
    OpenUrlAbstract/FREE Full Text
  103. 103.↵
    1. Skyschally A,
    2. Gres P,
    3. Heusch P,
    4. Martin C,
    5. Haude M,
    6. Erbel R,
    7. Schulz R,
    8. Heusch G.
    Preinfarction angina: no interference of coronary microembolization with acute ischemic preconditioning. J Mol Cell Cardiol. 2005;39:355–361. doi: 10.1016/j.yjmcc.2005.04.003.
    OpenUrlCrossRefPubMed
  104. 104.↵
    1. Skyschally A,
    2. Walter B,
    3. Heusch G.
    Coronary microembolization during early reperfusion: infarct extension, but protection by ischaemic postconditioning. Eur Heart J. 2013;34:3314–3321. doi: 10.1093/eurheartj/ehs434.
    OpenUrlAbstract/FREE Full Text
  105. 105.↵
    1. Herrmann J,
    2. Haude M,
    3. Lerman A,
    4. Schulz R,
    5. Volbracht L,
    6. Ge J,
    7. Schmermund A,
    8. Wieneke H,
    9. von Birgelen C,
    10. Eggebrecht H,
    11. Baumgart D,
    12. Heusch G,
    13. Erbel R.
    Abnormal coronary flow velocity reserve after coronary intervention is associated with cardiac marker elevation. Circulation. 2001;103:2339–2345.
    OpenUrlAbstract/FREE Full Text
  106. 106.↵
    1. Skyschally A,
    2. Schulz R,
    3. Erbel R,
    4. Heusch G.
    Reduced coronary and inotropic reserves with coronary microembolization. Am J Physiol Heart Circ Physiol. 2002;282:H611–H614. doi: 10.1152/ajpheart.00797.2001.
    OpenUrlAbstract/FREE Full Text
  107. 107.↵
    1. Baim DS,
    2. Wahr D,
    3. George B,
    4. Leon MB,
    5. Greenberg J,
    6. Cutlip DE,
    7. Kaya U,
    8. Popma JJ,
    9. Ho KK,
    10. Kuntz RE,
    11. Saphenous vein graft Angioplasty Free of Emboli Randomized (SAFER) Trial Investigators
    . Randomized trial of a distal embolic protection device during percutaneous intervention of saphenous vein aorto-coronary bypass grafts. Circulation. 2002;105:1285–1290.
    OpenUrlAbstract/FREE Full Text
  108. 108.↵
    1. Lins M,
    2. Heuer H,
    3. Haude M,
    4. Braun P,
    5. Stahl F,
    6. Franz N,
    7. Simon R,
    8. FIRST Trial Investigators
    . Distal embolic protection during percutaneous intervention of aorto-coronary venous bypass grafts: the FIRST Trial. Clin Res Cardiol. 2007;96:738–742. doi: 10.1007/s00392-007-0553-5.
    OpenUrlCrossRefPubMed
  109. 109.↵
    1. Sheridan FM,
    2. Dauber IM,
    3. McMurtry IF,
    4. Lesnefsky EJ,
    5. Horwitz LD.
    Role of leukocytes in coronary vascular endothelial injury due to ischemia and reperfusion. Circ Res. 1991;69:1566–1574.
    OpenUrlAbstract/FREE Full Text
  110. 110.↵
    1. Kogaki S,
    2. Sawa Y,
    3. Sano T,
    4. Matsushita T,
    5. Ohata T,
    6. Kurotobi S,
    7. Tojo SJ,
    8. Matsuda H,
    9. Okada S.
    Selectin on activated platelets enhances neutrophil endothelial adherence in myocardial reperfusion injury. Cardiovasc Res. 1999;43:968–973.
    OpenUrlAbstract/FREE Full Text
  111. 111.↵
    1. Kupatt C,
    2. Wichels R,
    3. Horstkotte J,
    4. Krombach F,
    5. Habazettl H,
    6. Boekstegers P.
    Molecular mechanisms of platelet-mediated leukocyte recruitment during myocardial reperfusion. J Leukoc Biol. 2002;72:455–461.
    OpenUrlAbstract/FREE Full Text
  112. 112.↵
    1. Barrabés JA,
    2. Garcia-Dorado D,
    3. Mirabet M,
    4. Inserte J,
    5. Agulló L,
    6. Soriano B,
    7. Massaguer A,
    8. Padilla F,
    9. Lidón RM,
    10. Soler-Soler J.
    Antagonism of selectin function attenuates microvascular platelet deposition and platelet-mediated myocardial injury after transient ischemia. J Am Coll Cardiol. 2005;45:293–299. doi: 10.1016/j.jacc.2004.09.068.
    OpenUrlCrossRefPubMed
  113. 113.↵
    1. Chukwuemeka AO,
    2. Brown KA,
    3. Venn GE,
    4. Chambers DJ.
    Changes in P-selectin expression on cardiac microvessels in blood-perfused rat hearts subjected to ischemia-reperfusion. Ann Thorac Surg. 2005;79:204–211. doi: 10.1016/j.athoracsur.2004.06.105.
    OpenUrlCrossRefPubMed
  114. 114.↵
    1. Barrabés JA,
    2. Mirabet M,
    3. Agulló L,
    4. Figueras J,
    5. Pizcueta P,
    6. Garcia-Dorado D.
    Platelet deposition in remote cardiac regions after coronary occlusion. Eur J Clin Invest. 2007;37:939–946. doi: 10.1111/j.1365-2362.2007.01883.x.
    OpenUrlCrossRefPubMed
  115. 115.↵
    1. Barrabés JA,
    2. Inserte J,
    3. Agulló L,
    4. Alonso A,
    5. Mirabet M,
    6. Garcia-Dorado D.
    Microvascular thrombosis: an exciting but elusive therapeutic target in reperfused acute myocardial infarction. Cardiovasc Hematol Disord Drug Targets. 2010;10:273–283.
    OpenUrlCrossRefPubMed
  116. 116.↵
    1. Driesen RB,
    2. Zalewski J,
    3. Vanden Driessche N,
    4. Vermeulen K,
    5. Bogaert J,
    6. Sipido KR,
    7. Van de Werf F,
    8. Claus P.
    Histological correlate of a cardiac magnetic resonance imaged microvascular obstruction in a porcine model of ischemia-reperfusion. Cardiovasc Pathol. 2012;21:129–131. doi: 10.1016/j.carpath.2011.07.008.
    OpenUrlCrossRefPubMed
  117. 117.↵
    1. Higginson LA,
    2. White F,
    3. Heggtveit HA,
    4. Sanders TM,
    5. Bloor CM,
    6. Covell JW.
    Determinants of myocardial hemorrhage after coronary reperfusion in the anesthetized dog. Circulation. 1982;65:62–69.
    OpenUrlAbstract/FREE Full Text
  118. 118.↵
    1. Higginson LA,
    2. Beanlands DS,
    3. Nair RC,
    4. Temple V,
    5. Sheldrick K.
    The time course and characterization of myocardial hemorrhage after coronary reperfusion in the anesthetized dog. Circulation. 1983;67:1024–1031.
    OpenUrlAbstract/FREE Full Text
  119. 119.↵
    1. Beek AM,
    2. Nijveldt R,
    3. van Rossum AC.
    Intramyocardial hemorrhage and microvascular obstruction after primary percutaneous coronary intervention. Int J Cardiovasc Imaging. 2010;26:49–55. doi: 10.1007/s10554-009-9499-1.
    OpenUrlCrossRefPubMed
  120. 120.↵
    1. Marra MP,
    2. Cacciavillani L,
    3. Corbetti F,
    4. Tarantini G,
    5. Ramondo AB,
    6. Napodano M,
    7. Basso C,
    8. Lacognata C,
    9. Marzari A,
    10. Maddalena F,
    11. Iliceto S.
    The contribution of intramyocardial hemorrhage to the “no-reflow phenomenon”: a study performed by cardiac magnetic resonance. Echocardiography. 2010;27:1120–1129. doi: 10.1111/j.1540-8175.2010.01213.x.
    OpenUrlCrossRefPubMed
  121. 121.↵
    1. Bonanad C,
    2. Ruiz-Sauri A,
    3. Forteza MJ,
    4. et al
    . Microvascular obstruction in the right ventricle in reperfused anterior myocardial infarction. Macroscopic and pathologic evidence in a swine model. Thromb Res. 2013;132:592–598. doi: 10.1016/j.thromres.2013.08.009.
    OpenUrlCrossRefPubMed
  122. 122.↵
    1. Robbers LF,
    2. Eerenberg ES,
    3. Teunissen PF,
    4. Jansen MF,
    5. Hollander MR,
    6. Horrevoets AJ,
    7. Knaapen P,
    8. Nijveldt R,
    9. Heymans MW,
    10. Levi MM,
    11. van Rossum AC,
    12. Niessen HW,
    13. Marcu CB,
    14. Beek AM,
    15. van Royen N.
    Magnetic resonance imaging-defined areas of microvascular obstruction after acute myocardial infarction represent microvascular destruction and haemorrhage. Eur Heart J. 2013;34:2346–2353. doi: 10.1093/eurheartj/eht100.
    OpenUrlAbstract/FREE Full Text
  123. 123.↵
    1. Prasad A,
    2. Gersh BJ,
    3. Mehran R,
    4. Brodie BR,
    5. Brener SJ,
    6. Dizon JM,
    7. Lansky AJ,
    8. Witzenbichler B,
    9. Kornowski R,
    10. Guagliumi G,
    11. Dudek D,
    12. Stone GW.
    Effect of ischemia duration and door-to-balloon time on myocardial perfusion in ST-segment elevation myocardial infarction: an analysis from HORIZONS-AMI trial (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction). JACC Cardiovasc Interv. 2015;8:1966–1974. doi: 10.1016/j.jcin.2015.08.031.
    OpenUrlCrossRefPubMed
  124. 124.↵
    1. Niccoli G,
    2. Scalone G,
    3. Lerman A,
    4. Crea F.
    Coronary microvascular obstruction in acute myocardial infarction. Eur Heart J. 2016;37:1024–1033. doi: 10.1093/eurheartj/ehv484.
    OpenUrlAbstract/FREE Full Text
  125. 125.↵
    1. Ndrepepa G,
    2. Tiroch K,
    3. Fusaro M,
    4. Keta D,
    5. Seyfarth M,
    6. Byrne RA,
    7. Pache J,
    8. Alger P,
    9. Mehilli J,
    10. Schömig A,
    11. Kastrati A.
    5-year prognostic value of no-reflow phenomenon after percutaneous coronary intervention in patients with acute myocardial infarction. J Am Coll Cardiol. 2010;55:2383–2389. doi: 10.1016/j.jacc.2009.12.054.
    OpenUrlCrossRefPubMed
  126. 126.↵
    1. Betgem RP,
    2. de Waard GA,
    3. Nijveldt R,
    4. Beek AM,
    5. Escaned J,
    6. van Royen N.
    Intramyocardial haemorrhage after acute myocardial infarction. Nat Rev Cardiol. 2015;12:156–167. doi: 10.1038/nrcardio.2014.188.
    OpenUrlPubMed
  127. 127.↵
    1. Laude K,
    2. Beauchamp P,
    3. Thuillez C,
    4. Richard V.
    Endothelial protective effects of preconditioning. Cardiovasc Res. 2002;55:466–473.
    OpenUrlAbstract/FREE Full Text
  128. 128.↵
    1. Di Napoli P,
    2. Di Muzio M,
    3. Contegiacomo G,
    4. Tiloca P,
    5. Spoletini L,
    6. Di Crecchio A,
    7. Gallina S,
    8. Barsotti A.
    [Ischemic preconditioning of the myocardium: the role of changes in the permeability of the coronary microcirculation]. Cardiologia. 1997;42:59–67.
    OpenUrlPubMed
  129. 129.↵
    1. Bauer B,
    2. Simkhovich BZ,
    3. Kloner RA,
    4. Przyklenk K.
    Does preconditioning protect the coronary vasculature from subsequent ischemia/reperfusion injury? Circulation. 1993;88:659–672.
    OpenUrlAbstract/FREE Full Text
  130. 130.↵
    1. Loke KE,
    2. Woodman OL.
    Preconditioning improves myocardial function and reflow, but not vasodilator reactivity, after ischaemia and reperfusion in anaesthetized dogs. Clin Exp Pharmacol Physiol. 1998;25:552–558.
    OpenUrlCrossRefPubMed
  131. 131.↵
    1. Richard V,
    2. Kaeffer N,
    3. Tron C,
    4. Thuillez C.
    Ischemic preconditioning protects against coronary endothelial dysfunction induced by ischemia and reperfusion. Circulation. 1994;89:1254–1261.
    OpenUrlAbstract/FREE Full Text
  132. 132.↵
    1. Bouchard JF,
    2. Lamontagne D.
    Mechanisms of protection afforded by preconditioning to endothelial function against ischemic injury. Am J Physiol. 1996;271:H1801–H1806.
    OpenUrl
  133. 133.↵
    1. Bouchard JF,
    2. Chouinard J,
    3. Lamontagne D.
    Role of kinins in the endothelial protective effect of ischaemic preconditioning. Br J Pharmacol. 1998;123:413–420. doi: 10.1038/sj.bjp.0701619.
    OpenUrlCrossRefPubMed
  134. 134.↵
    1. Kurzelewski M,
    2. Czarnowska E,
    3. Maczewski M,
    4. Beresewicz A.
    Effect of ischemic preconditioning on endothelial dysfunction and granulocyte adhesion in isolated guinea-pig hearts subjected to ischemia/reperfusion. J Physiol Pharmacol. 1999;50:617–628.
    OpenUrlPubMed
  135. 135.↵
    1. Thourani VH,
    2. Nakamura M,
    3. Duarte IG,
    4. Bufkin BL,
    5. Zhao ZQ,
    6. Jordan JE,
    7. Shearer ST,
    8. Guyton RA,
    9. Vinten-Johansen J.
    Ischemic preconditioning attenuates postischemic coronary artery endothelial dysfunction in a model of minimally invasive direct coronary artery bypass grafting. J Thorac Cardiovasc Surg. 1999;117:383–389. doi: 10.1016/S0022-5223(99)70437-X.
    OpenUrlCrossRefPubMed
  136. 136.↵
    1. Merkus D,
    2. Stepp DW,
    3. Jones DW,
    4. Nishikawa Y,
    5. Chilian WM.
    Adenosine preconditions against endothelin-induced constriction of coronary arterioles. Am J Physiol Heart Circ Physiol. 2000;279:H2593–H2597.
    OpenUrlAbstract/FREE Full Text
  137. 137.↵
    1. Tofukuji M,
    2. Metais C,
    3. Li J,
    4. Hariawala MD,
    5. Franklin A,
    6. Vassileva C,
    7. Li J,
    8. Simons M,
    9. Sellke FW.
    Effects of ischemic preconditioning on myocardial perfusion, function, and microvascular regulation. Circulation. 1998;98:II-197–II-205.
    OpenUrl
  138. 138.↵
    1. Gattullo D,
    2. Linden RJ,
    3. Losano G,
    4. Pagliaro P,
    5. Westerhof N.
    Ischaemic preconditioning changes the pattern of coronary reactive hyperaemia in the goat: role of adenosine and nitric oxide. Cardiovasc Res. 1999;42:57–64.
    OpenUrlAbstract/FREE Full Text
  139. 139.↵
    1. Posa A,
    2. Pavo N,
    3. Hemetsberger R,
    4. Csonka C,
    5. Csont T,
    6. Ferdinandy P,
    7. Petrási Z,
    8. Varga C,
    9. Pavo IJ,
    10. Laszlo F Jr.,
    11. Huber K,
    12. Gyöngyösi M.
    Protective effect of ischaemic preconditioning on ischaemia/reperfusion-induced microvascular obstruction determined by on-line measurements of coronary pressure and blood flow in pigs. Thromb Haemost. 2010;103:450–460. doi: 10.1160/TH09-03-0165.
    OpenUrlPubMed
  140. 140.↵
    1. Kaeffer N,
    2. Richard V,
    3. François A,
    4. Lallemand F,
    5. Henry JP,
    6. Thuillez C.
    Preconditioning prevents chronic reperfusion-induced coronary endothelial dysfunction in rats. Am J Physiol. 1996;271:H842–H849.
    OpenUrl
  141. 141.↵
    1. Laude K,
    2. Favre J,
    3. Thuillez C,
    4. Richard V.
    NO produced by endothelial NO synthase is a mediator of delayed preconditioning-induced endothelial protection. Am J Physiol Heart Circ Physiol. 2003;284:H2053–H2060. doi: 10.1152/ajpheart.00627.2002.
    OpenUrlAbstract/FREE Full Text
  142. 142.↵
    1. Kim SJ,
    2. Zhang X,
    3. Xu X,
    4. Chen A,
    5. Gonzalez JB,
    6. Koul S,
    7. Vijayan K,
    8. Crystal GJ,
    9. Vatner SF,
    10. Hintze TH.
    Evidence for enhanced eNOS function in coronary microvessels during the second window of protection. Am J Physiol Heart Circ Physiol. 2007;292:H2152–H2158. doi: 10.1152/ajpheart.00326.2006.
    OpenUrlAbstract/FREE Full Text
  143. 143.↵
    1. Kaeffer N,
    2. Richard V,
    3. Thuillez C.
    Delayed coronary endothelial protection 24 hours after preconditioning: role of free radicals. Circulation. 1997;96:2311–2316.
    OpenUrlAbstract/FREE Full Text
  144. 144.↵
    1. Matsuda N,
    2. Morgan KG,
    3. Sellke FW.
    Preconditioning improves cardioplegia-related coronary microvascular smooth muscle hypercontractility: role of KATP channels. J Thorac Cardiovasc Surg. 1999;118:438–445. doi: 10.1016/S0022-5223(99)70180-7.
    OpenUrlCrossRefPubMed
  145. 145.↵
    1. Skyschally A,
    2. Schulz R,
    3. Gres P,
    4. Konietzka I,
    5. Martin C,
    6. Haude M,
    7. Erbel R,
    8. Heusch G.
    Coronary microembolization does not induce acute preconditioning against infarction in pigs-the role of adenosine. Cardiovasc Res. 2004;63:313–322. doi: 10.1016/j.cardiores.2004.04.003.
    OpenUrlAbstract/FREE Full Text
  146. 146.↵
    1. Skyschally A,
    2. Gres P,
    3. Hoffmann S,
    4. Haude M,
    5. Erbel R,
    6. Schulz R,
    7. Heusch G.
    Bidirectional role of tumor necrosis factor-alpha in coronary microembolization: progressive contractile dysfunction versus delayed protection against infarction. Circ Res. 2007;100:140–146. doi: 10.1161/01.RES.0000255031.15793.86.
    OpenUrlAbstract/FREE Full Text
  147. 147.↵
    1. Heusch G.
    Nitroglycerin and delayed preconditioning in humans: yet another new mechanism for an old drug? Circulation. 2001;103:2876–2878.
    OpenUrlFREE Full Text
  148. 148.↵
    1. Rezkalla SH,
    2. Kloner RA.
    Ischemic preconditioning and preinfarction angina in the clinical arena. Nat Clin Pract Cardiovasc Med. 2004;1:96–102. doi: 10.1038/ncpcardio0047.
    OpenUrlCrossRefPubMed
  149. 149.↵
    1. Scalone G,
    2. Aurigemma C,
    3. Tomai F,
    4. Corvo P,
    5. Battipaglia I,
    6. Lanza GA,
    7. Crea F.
    Effect of pre-infarction angina on platelet reactivity in acute myocardial infarction. Int J Cardiol. 2013;167:51–56. doi: 10.1016/j.ijcard.2011.11.085.
    OpenUrlCrossRefPubMed
  150. 150.↵
    1. Colonna P,
    2. Cadeddu C,
    3. Montisci R,
    4. Ruscazio M,
    5. Selem AH,
    6. Chen L,
    7. Onnis E,
    8. Meloni L,
    9. Iliceto S.
    Reduced microvascular and myocardial damage in patients with acute myocardial infarction and preinfarction angina. Am Heart J. 2002;144:796–803.
    OpenUrlCrossRefPubMed
  151. 151.↵
    1. Niccoli G,
    2. Scalone G,
    3. Cosentino N,
    4. Fabretti A,
    5. Mirizzi AM,
    6. Gramegna M,
    7. Panebianco M,
    8. Roberto M,
    9. Crea F.
    Protective effect of pre-infarction angina on microvascular obstruction after primary percutaneous coronary intervention is blunted in humans by cardiovascular risk factors. Circ J. 2014;78:1935–1941.
    OpenUrlCrossRefPubMed
  152. 152.↵
    1. Hale SL,
    2. Mehra A,
    3. Leeka J,
    4. Kloner RA.
    Postconditioning fails to improve no reflow or alter infarct size in an open-chest rabbit model of myocardial ischemia-reperfusion. Am J Physiol Heart Circ Physiol. 2008;294:H421–H425. doi: 10.1152/ajpheart.00962.2007.
    OpenUrlAbstract/FREE Full Text
  153. 153.↵
    1. Bodi V,
    2. Ruiz-Nodar JM,
    3. Feliu E,
    4. et al
    . Effect of ischemic postconditioning on microvascular obstruction in reperfused myocardial infarction. Results of a randomized study in patients and of an experimental model in swine. Int J Cardiol. 2014;175:138–146. doi: 10.1016/j.ijcard.2014.05.003.
    OpenUrlCrossRefPubMed
  154. 154.↵
    1. Skyschally A,
    2. Kleinbongard P,
    3. Heusch G.
    Local and remote ischemic preconditioning reduces myocardial infarct size and microvascular obstruction during reperfusion, whereas ischemic postconditioning only reduces infarct size. Clin Res Cardiol. 2016;105 Suppl. 1:V845.
    OpenUrl
  155. 155.↵
    1. Zhao JL,
    2. Yang YJ,
    3. You SJ,
    4. Cui CJ,
    5. Gao RL.
    Different effects of postconditioning on myocardial no-reflow in the normal and hypercholesterolemic mini-swines. Microvasc Res. 2007;73:137–142. doi: 10.1016/j.mvr.2006.09.002.
    OpenUrlCrossRefPubMed
  156. 156.↵
    1. Ma X,
    2. Zhang X,
    3. Li C,
    4. Luo M.
    Effect of postconditioning on coronary blood flow velocity and endothelial function and LV recovery after myocardial infarction. J Interv Cardiol. 2006;19:367–375. doi: 10.1111/j.1540-8183.2006.00191.x.
    OpenUrlCrossRefPubMed
  157. 157.↵
    1. Ma XJ,
    2. Zhang XH,
    3. Li CM,
    4. Luo M.
    Effect of postconditioning on coronary blood flow velocity and endothelial function in patients with acute myocardial infarction. Scand Cardiovasc J. 2006;40:327–333. doi: 10.1080/14017430601047864.
    OpenUrlCrossRefPubMed
  158. 158.↵
    1. Yang XC,
    2. Liu Y,
    3. Wang LF,
    4. Cui L,
    5. Wang T,
    6. Ge YG,
    7. Wang HS,
    8. Li WM,
    9. Xu L,
    10. Ni ZH,
    11. Liu SH,
    12. Zhang L,
    13. Jia HM,
    14. Vinten-Johansen J,
    15. Zhao ZQ.
    Reduction in myocardial infarct size by postconditioning in patients after percutaneous coronary intervention. J Invasive Cardiol. 2007;19:424–430.
    OpenUrlPubMed
  159. 159.↵
    1. Laskey WK,
    2. Yoon S,
    3. Calzada N,
    4. 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. 2008;72:212–220. doi: 10.1002/ccd.21583.
    OpenUrlCrossRefPubMed
  160. 160.↵
    1. Garcia S,
    2. Henry TD,
    3. Wang YL,
    4. Chavez IJ,
    5. Pedersen WR,
    6. Lesser JR,
    7. Shroff GR,
    8. Moore L,
    9. Traverse JH.
    Long-term follow-up of patients undergoing postconditioning during ST-elevation myocardial infarction. J Cardiovasc Transl Res. 2011;4:92–98. doi: 10.1007/s12265-010-9252-0.
    OpenUrlCrossRefPubMed
  161. 161.↵
    1. Liu TK,
    2. Mishra AK,
    3. Ding FX.
    [Protective effect of ischemia postconditioning on reperfusion injury in patients with ST-segment elevation acute myocardial infarction]. Zhonghua Xin Xue Guan Bing Za Zhi. 2011;39:35–39.
    OpenUrlPubMed
  162. 162.↵
    1. Thuny F,
    2. Lairez O,
    3. Roubille F,
    4. et al
    . Post-conditioning reduces infarct size and edema in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2012;59:2175–2181. doi: 10.1016/j.jacc.2012.03.026.
    OpenUrlCrossRefPubMed
  163. 163.↵
    1. Mewton N,
    2. Thibault H,
    3. Roubille F,
    4. et al
    . Postconditioning attenuates no-reflow in STEMI patients. Basic Res Cardiol. 2013;108:383. doi: 10.1007/s00395-013-0383-8.
    OpenUrlCrossRefPubMed
  164. 164.↵
    1. Araszkiewicz A,
    2. Grygier M,
    3. Pyda M,
    4. Rajewska J,
    5. Michalak M,
    6. Lesiak M,
    7. Grajek S.
    Postconditioning reduces enzymatic infarct size and improves microvascular reperfusion in patients with ST-segment elevation myocardial infarction. Cardiology. 2014;129:250–257. doi: 10.1159/000367965.
    OpenUrlCrossRefPubMed
  165. 165.↵
    1. Tarantini G,
    2. Favaretto E,
    3. Marra MP,
    4. Frigo AC,
    5. Napodano M,
    6. Cacciavillani L,
    7. Giovagnoni A,
    8. Renda P,
    9. De Biasio V,
    10. Plebani M,
    11. Mion M,
    12. Zaninotto M,
    13. Isabella G,
    14. Bilato C,
    15. Iliceto S.
    Postconditioning during coronary angioplasty in acute myocardial infarction: the POST-AMI trial. Int J Cardiol. 2012;162:33–38. doi: 10.1016/j.ijcard.2012.03.136.
    OpenUrlCrossRefPubMed
  166. 166.↵
    1. Ugata Y,
    2. Nakamura T,
    3. Taniguchi Y,
    4. Ako J,
    5. Momomura S.
    Effect of postconditioning in patients with ST-elevation acute myocardial infarction. Cardiovasc Interv Ther. 2012;27:14–18. doi: 10.1007/s12928-011-0077-9.
    OpenUrlCrossRefPubMed
  167. 167.↵
    1. Dwyer NB,
    2. Mikami Y,
    3. Hilland D,
    4. Aljizeeri A,
    5. Friedrich MG,
    6. Traboulsi M,
    7. Anderson TJ.
    No cardioprotective benefit of ischemic postconditioning in patients with ST-segment elevation myocardial infarction. J Interv Cardiol. 2013;26:482–490. doi: 10.1111/joic.12064.
    OpenUrlCrossRefPubMed
  168. 168.↵
    1. Hahn JY,
    2. Song YB,
    3. Kim EK,
    4. et al
    . Ischemic postconditioning during primary percutaneous coronary intervention: the effects of postconditioning on myocardial reperfusion in patients with ST-segment elevation myocardial infarction (POST) randomized trial. Circulation. 2013;128:1889–1896. doi: 10.1161/CIRCULATIONAHA.113.001690.
    OpenUrlAbstract/FREE Full Text
  169. 169.↵
    1. Eitel I,
    2. Stiermaier T,
    3. Rommel KP,
    4. Fuernau G,
    5. Sandri M,
    6. Mangner N,
    7. Linke A,
    8. Erbs S,
    9. Lurz P,
    10. Boudriot E,
    11. Mende M,
    12. Desch S,
    13. Schuler G,
    14. Thiele H.
    Cardioprotection by combined intrahospital remote ischaemic perconditioning and postconditioning in ST-elevation myocardial infarction: the randomized LIPSIA CONDITIONING trial. Eur Heart J. 2015;36:3049–3057. doi: 10.1093/eurheartj/ehv463.
    OpenUrlAbstract/FREE Full Text
  170. 170.↵
    1. Kim EK,
    2. Hahn JY,
    3. Song YB,
    4. Lee SC,
    5. Choi JH,
    6. Choi SH,
    7. Lee SH,
    8. Choe YH,
    9. Gwon HC.
    Effect of ischemic postconditioning on myocardial salvage in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: cardiac magnetic resonance substudy of the POST randomized trial. Int J Cardiovasc Imaging. 2015;31:629–637. doi: 10.1007/s10554-015-0589-y.
    OpenUrlCrossRefPubMed
  171. 171.↵
    1. Loubeyre C,
    2. Morice MC,
    3. Lefèvre T,
    4. Piéchaud JF,
    5. Louvard Y,
    6. Dumas P.
    A randomized comparison of direct stenting with conventional stent implantation in selected patients with acute myocardial infarction. J Am Coll Cardiol. 2002;39:15–21.
    OpenUrlPubMed
  172. 172.↵
    1. Roubille F,
    2. Lairez O,
    3. Mewton N,
    4. Rioufol G,
    5. Ranc S,
    6. Sanchez I,
    7. Cung TT,
    8. Elbaz M,
    9. Piot C,
    10. Ovize M.
    Cardioprotection by clopidogrel in acute ST-elevated myocardial infarction patients: a retrospective analysis. Basic Res Cardiol. 2012;107:275. doi: 10.1007/s00395-012-0275-3.
    OpenUrlCrossRefPubMed
  173. 173.↵
    1. Cohen MV,
    2. Downey JM.
    Status of P2Y12 treatment must be considered in evaluation of myocardial ischaemia/reperfusion injury. Cardiovasc Res. 2015;106:8. doi: 10.1093/cvr/cvv051.
    OpenUrlFREE Full Text
  174. 174.↵
    1. Iliodromitis EK,
    2. Cohen MV,
    3. Dagres N,
    4. Andreadou I,
    5. Kremastinos DT,
    6. Downey JM.
    What is wrong with cardiac conditioning? We may be shooting at moving targets. J Cardiovasc Pharmacol Ther. 2015;20:357–369. doi: 10.1177/1074248414566459.
    OpenUrlAbstract/FREE Full Text
  175. 175.↵
    1. Przyklenk K,
    2. Bauer B,
    3. Ovize M,
    4. Kloner RA,
    5. Whittaker P.
    Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation. 1993;87:893–899.
    OpenUrlAbstract/FREE Full Text
  176. 176.↵
    1. Heusch G,
    2. Bøtker HE,
    3. Przyklenk K,
    4. Redington A,
    5. Yellon D.
    Remote ischemic conditioning. J Am Coll Cardiol. 2015;65:177–195. doi: 10.1016/j.jacc.2014.10.031.
    OpenUrlCrossRefPubMed
  177. 177.↵
    1. Shimizu M,
    2. Konstantinov IE,
    3. Kharbanda RK,
    4. Cheung MH,
    5. Redington AN.
    Effects of intermittent lower limb ischaemia on coronary blood flow and coronary resistance in pigs. Acta Physiol (Oxf). 2007;190:103–109. doi: 10.1111/j.1748-1716.2007.01667.x.
    OpenUrlCrossRefPubMed
  178. 178.↵
    1. Kono Y,
    2. Fukuda S,
    3. Hanatani A,
    4. Nakanishi K,
    5. Otsuka K,
    6. Taguchi H,
    7. Shimada K.
    Remote ischemic conditioning improves coronary microcirculation in healthy subjects and patients with heart failure. Drug Des Devel Ther. 2014;8:1175–1181. doi: 10.2147/DDDT.S68715.
    OpenUrlPubMed
  179. 179.↵
    1. Hoole SP,
    2. Heck PM,
    3. White PA,
    4. Khan SN,
    5. O’Sullivan M,
    6. Clarke SC,
    7. Dutka DP.
    Remote ischemic preconditioning stimulus does not reduce microvascular resistance or improve myocardial blood flow in patients undergoing elective percutaneous coronary intervention. Angiology. 2009;60:403–411. doi: 10.1177/0003319708328921.
    OpenUrlAbstract/FREE Full Text
  180. 180.↵
    1. Bøtker HE,
    2. Kharbanda R,
    3. Schmidt MR,
    4. et al
    . Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet. 2010;375:727–734. doi: 10.1016/S0140-6736(09)62001-8.
    OpenUrlCrossRefPubMed
  181. 181.↵
    1. White SK,
    2. Frohlich GM,
    3. Sado DM,
    4. Maestrini V,
    5. Fontana M,
    6. Treibel TA,
    7. Tehrani S,
    8. Flett AS,
    9. Meier P,
    10. Ariti C,
    11. Davies JR,
    12. Moon JC,
    13. Yellon DM,
    14. Hausenloy DJ.
    Remote ischemic conditioning reduces myocardial infarct size and edema in patients with ST-segment elevation myocardial infarction. JACC Cardiovasc Interv. 2015;8:178–188. doi: 10.1016/j.jcin.2014.05.015.
    OpenUrlCrossRefPubMed
  182. 182.↵
    1. Crimi G,
    2. Pica S,
    3. Raineri C,
    4. et al
    . Remote ischemic post-conditioning of the lower limb during primary percutaneous coronary intervention safely reduces enzymatic infarct size in anterior myocardial infarction: a randomized controlled trial. JACC Cardiovasc Interv. 2013;6:1055–1063. doi: 10.1016/j.jcin.2013.05.011.
    OpenUrlCrossRefPubMed
  183. 183.↵
    1. Pryds K,
    2. Botker HE.
    Influence of pre-infarction angina and coronary collateral circulation on the efficacy of remote ischaemic conditioning in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. Eur Heart J Acute Cardiovasc Care. In press.
  184. 184.↵
    1. Shimizu M,
    2. Saxena P,
    3. Konstantinov IE,
    4. Cherepanov V,
    5. Cheung MM,
    6. Wearden P,
    7. Zhangdong H,
    8. Schmidt M,
    9. Downey GP,
    10. Redington AN.
    Remote ischemic preconditioning decreases adhesion and selectively modifies functional responses of human neutrophils. J Surg Res. 2010;158:155–161. doi: 10.1016/j.jss.2008.08.010.
    OpenUrlCrossRefPubMed
  185. 185.↵
    1. Stazi A,
    2. Scalone G,
    3. Laurito M,
    4. Milo M,
    5. Pelargonio G,
    6. Narducci ML,
    7. Parrinello R,
    8. Figliozzi S,
    9. Bencardino G,
    10. Perna F,
    11. Lanza GA,
    12. Crea F.
    Effect of remote ischemic preconditioning on platelet activation and reactivity induced by ablation for atrial fibrillation. Circulation. 2014;129:11–17. doi: 10.1161/CIRCULATIONAHA.113.005336.
    OpenUrlAbstract/FREE Full Text
  186. 186.↵
    1. Lanza GA,
    2. Stazi A,
    3. Villano A,
    4. Torrini F,
    5. Milo M,
    6. Laurito M,
    7. Flego D,
    8. Aurigemma C,
    9. Liuzzo G,
    10. Crea F.
    Effect of remote ischemic preconditioning on platelet activation induced by coronary procedures. Am J Cardiol. 2016;117:359–365. doi: 10.1016/j.amjcard.2015.10.056.
    OpenUrlCrossRefPubMed
  187. 187.↵
    1. Kleinbongard P,
    2. Schulz R,
    3. Rassaf T,
    4. et al
    . Red blood cells express a functional endothelial nitric oxide synthase. Blood. 2006;107:2943–2951. doi: 10.1182/blood-2005-10-3992.
    OpenUrlAbstract/FREE Full Text
  188. 188.↵
    1. Grau M,
    2. Kollikowski A,
    3. Bloch W.
    Remote ischemia preconditioning increases red blood cell deformability through red blood cell-nitric oxide synthase activation [published online ahead of print January 27, 2016]. Clin Hemorheol Microcirc. 2016.
  189. 189.↵
    1. Heusch G,
    2. Libby P,
    3. Gersh B,
    4. Yellon D,
    5. Böhm M,
    6. Lopaschuk G,
    7. Opie L.
    Cardiovascular remodelling in coronary artery disease and heart failure. Lancet. 2014;383:1933–1943. doi: 10.1016/S0140-6736(14)60107-0.
    OpenUrlCrossRefPubMed
  190. 190.↵
    1. Ferdinandy P,
    2. Hausenloy DJ,
    3. Heusch G,
    4. Baxter GF,
    5. Schulz R.
    Interaction of risk factors, comorbidities, and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol Rev. 2014;66:1142–1174. doi: 10.1124/pr.113.008300.
    OpenUrlAbstract/FREE Full Text
  191. 191.↵
    1. Schwartz Longacre L,
    2. Kloner RA,
    3. Arai AE,
    4. et al.,
    5. National Heart, Lung, and Blood Institute, National Institutes of Health
    . New horizons in cardioprotection: recommendations from the 2010 National Heart, Lung, and Blood Institute Workshop. Circulation. 2011;124:1172–1179. doi: 10.1161/CIRCULATIONAHA.111.032698.
    OpenUrlFREE Full Text
  192. 192.↵
    1. Jones SP,
    2. Tang XL,
    3. Guo Y,
    4. et al
    . The NHLBI-sponsored Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR): a new paradigm for rigorous, accurate, and reproducible evaluation of putative infarct-sparing interventions in mice, rabbits, and pigs. Circ Res. 2015;116:572–586. doi: 10.1161/CIRCRESAHA.116.305462.
    OpenUrlAbstract/FREE Full Text
  193. 193.↵
    1. Yetgin T,
    2. Uitterdijk A,
    3. Te Lintel Hekkert M,
    4. Merkus D,
    5. Krabbendam-Peters I,
    6. van Beusekom HM,
    7. Falotico R,
    8. Serruys PW,
    9. Manintveld OC,
    10. van Geuns RJ,
    11. Zijlstra F,
    12. Duncker DJ.
    Limitation of infarct size and no-reflow by intracoronary adenosine depends critically on dose and duration. JACC Cardiovasc Interv. 2015;8:1990–1999. doi: 10.1016/j.jcin.2015.08.033.
    OpenUrlCrossRefPubMed
  194. 194.↵
    1. Zalewski J,
    2. Claus P,
    3. Bogaert J,
    4. Driessche NV,
    5. Driesen RB,
    6. Galan DT,
    7. Sipido KR,
    8. Buszman P,
    9. Milewski K,
    10. Van de Werf F.
    Cyclosporine A reduces microvascular obstruction and preserves left ventricular function deterioration following myocardial ischemia and reperfusion. Basic Res Cardiol. 2015;110:18. doi: 10.1007/s00395-015-0475-8.
    OpenUrlCrossRefPubMed
  195. 195.↵
    1. Sattler K,
    2. Gräler M,
    3. Keul P,
    4. Weske S,
    5. Reimann CM,
    6. Jindrová H,
    7. Kleinbongard P,
    8. Sabbadini R,
    9. Bröcker-Preuss M,
    10. Erbel R,
    11. Heusch G,
    12. Levkau B.
    Defects of high-density lipoproteins in coronary artery disease caused by low sphingosine-1-phosphate content: correction by sphingosine-1-phosphate-loading. J Am Coll Cardiol. 2015;66:1470–1485. doi: 10.1016/j.jacc.2015.07.057.
    OpenUrlCrossRefPubMed
  196. 196.↵
    1. Vilahur G,
    2. Gutiérrez M,
    3. Casaní L,
    4. Cubedo J,
    5. Capdevila A,
    6. Pons-Llado G,
    7. Carreras F,
    8. Hidalgo A,
    9. Badimon L.
    Hypercholesterolemia abolishes high-density lipoprotein-related cardioprotective effects in the setting of myocardial infarction. J Am Coll Cardiol. 2015;66:2469–2470. doi: 10.1016/j.jacc.2015.08.901.
    OpenUrlCrossRefPubMed
  197. 197.↵
    1. Li XD,
    2. Yang YJ,
    3. Geng YJ,
    4. Cheng YT,
    5. Zhang HT,
    6. Zhao JL,
    7. Yuan JQ,
    8. Gao RL.
    The cardioprotection of simvastatin in reperfused swine hearts relates to the inhibition of myocardial edema by modulating aquaporins via the PKA pathway. Int J Cardiol. 2013;167:2657–2666. doi: 10.1016/j.ijcard.2012.06.121.
    OpenUrlCrossRefPubMed
  198. 198.↵
    1. Zhao JL,
    2. Yang YJ,
    3. Cui CJ,
    4. You SJ,
    5. Gao RL.
    Pretreatment with simvastatin reduces myocardial no-reflow by opening mitochondrial K(ATP) channel. Br J Pharmacol. 2006;149:243–249. doi: 10.1038/sj.bjp.0706862.
    OpenUrlCrossRefPubMed
  199. 199.↵
    1. Dokken BB,
    2. La Bonte LR,
    3. Davis-Gorman G,
    4. Teachey MK,
    5. Seaver N,
    6. McDonagh PF.
    Glucagon-like peptide-1 (GLP-1), immediately prior to reperfusion, decreases neutrophil activation and reduces myocardial infarct size in rodents. Horm Metab Res. 2011;43:300–305. doi: 10.1055/s-0031-1271777.
    OpenUrlCrossRefPubMed
  200. 200.↵
    1. Garcia-Dorado D,
    2. Théroux P,
    3. Munoz R,
    4. Alonso J,
    5. Elizaga J,
    6. Fernandez-Avilés F,
    7. Botas J,
    8. Solares J,
    9. Soriano J,
    10. Duran JM.
    Favorable effects of hyperosmotic reperfusion on myocardial edema and infarct size. Am J Physiol. 1992;262:H17–H22.
    OpenUrl
  201. 201.↵
    1. Uitterdijk A,
    2. Yetgin T,
    3. te Lintel Hekkert M,
    4. Sneep S,
    5. Krabbendam-Peters I,
    6. van Beusekom HM,
    7. Fischer TM,
    8. Cornelussen RN,
    9. Manintveld OC,
    10. Merkus D,
    11. Duncker DJ.
    Vagal nerve stimulation started just prior to reperfusion limits infarct size and no-reflow. Basic Res Cardiol. 2015;110:508. doi: 10.1007/s00395-015-0508-3.
    OpenUrlPubMed
  202. 202.↵
    1. Pierrakos CN,
    2. Bonios MJ,
    3. Drakos SG,
    4. Charitos EI,
    5. Tsolakis EJ,
    6. Ntalianis A,
    7. Nanas SN,
    8. Charitos CE,
    9. Nanas JN,
    10. Terrovitis JV.
    Mechanical assistance by intra-aortic balloon pump counterpulsation during reperfusion increases coronary blood flow and mitigates the no-reflow phenomenon: an experimental study. Artif Organs. 2011;35:867–874. doi: 10.1111/j.1525-1594.2011.01241.x.
    OpenUrlCrossRefPubMed
  203. 203.↵
    1. Pantsios C,
    2. Kapelios C,
    3. Vakrou S,
    4. Diakos N,
    5. Pozios I,
    6. Kontogiannis C,
    7. Nanas J,
    8. Malliaras K.
    Effect of elevated reperfusion pressure on “no reflow” area and infarct size in a porcine model of ischemia-reperfusion [published online ahead of print November 20, 2015]. J Cardiovasc Pharmacol Ther. 2015.
  204. 204.↵
    1. Herring MJ,
    2. Dai W,
    3. Hale SL,
    4. Kloner RA.
    Rapid induction of hypothermia by the ThermoSuit system profoundly reduces infarct size and anatomic zone of no reflow following ischemia-reperfusion in rabbit and rat hearts. J Cardiovasc Pharmacol Ther. 2015;20:193–202. doi: 10.1177/1074248414535664.
    OpenUrlAbstract/FREE Full Text
  205. 205.↵
    1. Hale SL,
    2. Herring MJ,
    3. Kloner RA.
    Delayed treatment with hypothermia protects against the no-reflow phenomenon despite failure to reduce infarct size. J Am Heart Assoc. 2013;2:e004234. doi: 10.1161/JAHA.112.004234.
    OpenUrlAbstract/FREE Full Text
  206. 206.↵
    1. Kanazawa H,
    2. Tseliou E,
    3. Malliaras K,
    4. et al
    . Cellular postconditioning: allogeneic cardiosphere-derived cells reduce infarct size and attenuate microvascular obstruction when administered after reperfusion in pigs with acute myocardial infarction. Circ Heart Fail. 2015;8:322–332. doi: 10.1161/CIRCHEARTFAILURE.114.001484.
    OpenUrlAbstract/FREE Full Text
  207. 207.↵
    1. Gerczuk PZ,
    2. Kloner RA.
    An update on cardioprotection: a review of the latest adjunctive therapies to limit myocardial infarction size in clinical trials. J Am Coll Cardiol. 2012;59:969–978. doi: 10.1016/j.jacc.2011.07.054.
    OpenUrlCrossRefPubMed
  208. 208.↵
    1. Dixon SR,
    2. Whitbourn RJ,
    3. Dae MW,
    4. Grube E,
    5. Sherman W,
    6. Schaer GL,
    7. Jenkins JS,
    8. Baim DS,
    9. Gibbons RJ,
    10. Kuntz RE,
    11. Popma JJ,
    12. Nguyen TT,
    13. O’Neill WW.
    Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction. J Am Coll Cardiol. 2002;40:1928–1934.
    OpenUrlCrossRefPubMed
  209. 209.↵
    1. Götberg M,
    2. Olivecrona GK,
    3. Koul S,
    4. Carlsson M,
    5. Engblom H,
    6. Ugander M,
    7. van der Pals J,
    8. Algotsson L,
    9. Arheden H,
    10. Erlinge D.
    A pilot study of rapid cooling by cold saline and endovascular cooling before reperfusion in patients with ST-elevation myocardial infarction. Circ Cardiovasc Interv. 2010;3:400–407. doi: 10.1161/CIRCINTERVENTIONS.110.957902.
    OpenUrlAbstract/FREE Full Text
  210. 210.↵
    1. Erlinge D,
    2. Götberg M,
    3. Lang I,
    4. et al
    . Rapid endovascular catheter core cooling combined with cold saline as an adjunct to percutaneous coronary intervention for the treatment of acute myocardial infarction. The CHILL-MI trial: a randomized controlled study of the use of central venous catheter core cooling combined with cold saline as an adjunct to percutaneous coronary intervention for the treatment of acute myocardial infarction. J Am Coll Cardiol. 2014;63:1857–1865. doi: 10.1016/j.jacc.2013.12.027.
    OpenUrlCrossRefPubMed
  211. 211.↵
    1. Nichol G,
    2. Strickland W,
    3. Shavelle D,
    4. et al.,
    5. VELOCITY Investigators
    . Prospective, multicenter, randomized, controlled pilot trial of peritoneal hypothermia in patients with ST-segment- elevation myocardial infarction. Circ Cardiovasc Interv. 2015;8:e001965. doi: 10.1161/CIRCINTERVENTIONS.114.001965.
    OpenUrlAbstract/FREE Full Text
  212. 212.↵
    1. O’Neill WW,
    2. Martin JL,
    3. Dixon SR,
    4. Bartorelli AL,
    5. Trabattoni D,
    6. Oemrawsingh PV,
    7. Atsma DE,
    8. Chang M,
    9. Marquardt W,
    10. Oh JK,
    11. Krucoff MW,
    12. Gibbons RJ,
    13. Spears JR,
    14. AMIHOT Investigators
    . Acute Myocardial Infarction with Hyperoxemic Therapy (AMIHOT): a prospective, randomized trial of intracoronary hyperoxemic reperfusion after percutaneous coronary intervention. J Am Coll Cardiol. 2007;50:397–405. doi: 10.1016/j.jacc.2007.01.099.
    OpenUrlCrossRefPubMed
  213. 213.↵
    1. Stone GW,
    2. Martin JL,
    3. de Boer MJ,
    4. Margheri M,
    5. Bramucci E,
    6. Blankenship JC,
    7. Metzger DC,
    8. Gibbons RJ,
    9. Lindsay BS,
    10. Weiner BH,
    11. Lansky AJ,
    12. Krucoff MW,
    13. Fahy M,
    14. Boscardin WJ,
    15. AMIHOT-II Trial Investigators
    . Effect of supersaturated oxygen delivery on infarct size after percutaneous coronary intervention in acute myocardial infarction. Circ Cardiovasc Interv. 2009;2:366–375. doi: 10.1161/CIRCINTERVENTIONS.108.840066.
    OpenUrlAbstract/FREE Full Text
  214. 214.↵
    1. Antoniucci D,
    2. Valenti R,
    3. Migliorini A,
    4. Parodi G,
    5. Memisha G,
    6. Santoro GM,
    7. Sciagrà R.
    Comparison of rheolytic thrombectomy before direct infarct artery stenting versus direct stenting alone in patients undergoing percutaneous coronary intervention for acute myocardial infarction. Am J Cardiol. 2004;93:1033–1035. doi: 10.1016/j.amjcard.2004.01.011.
    OpenUrlCrossRefPubMed
  215. 215.↵
    1. Kaltoft A,
    2. Bøttcher M,
    3. Nielsen SS,
    4. et al
    . Routine thrombectomy in percutaneous coronary intervention for acute ST-segment-elevation myocardial infarction: a randomized, controlled trial. Circulation. 2006;114:40–47. doi: 10.1161/CIRCULATIONAHA.105.595660.
    OpenUrlAbstract/FREE Full Text
  216. 216.↵
    1. Lipiecki J,
    2. Monzy S,
    3. Durel N,
    4. Cachin F,
    5. Chabrot P,
    6. Muliez A,
    7. Morand D,
    8. Maublant J,
    9. Ponsonnaille J.
    Effect of thrombus aspiration on infarct size and left ventricular function in high-risk patients with acute myocardial infarction treated by percutaneous coronary intervention. Results of a prospective controlled pilot study. Am Heart J. 2009;157:583.e1–583.e7. doi: 10.1016/j.ahj.2008.11.017.
    OpenUrlCrossRefPubMed
  217. 217.↵
    1. Sardella G,
    2. Mancone M,
    3. Bucciarelli-Ducci C,
    4. Agati L,
    5. Scardala R,
    6. Carbone I,
    7. Francone M,
    8. Di Roma A,
    9. Benedetti G,
    10. Conti G,
    11. Fedele F.
    Thrombus aspiration during primary percutaneous coronary intervention improves myocardial reperfusion and reduces infarct size: the EXPIRA (thrombectomy with export catheter in infarct-related artery during primary percutaneous coronary intervention) prospective, randomized trial. J Am Coll Cardiol. 2009;53:309–315. doi: 10.1016/j.jacc.2008.10.017.
    OpenUrlCrossRefPubMed
  218. 218.↵
    1. Migliorini A,
    2. Stabile A,
    3. Rodriguez AE,
    4. Gandolfo C,
    5. Rodriguez Granillo AM,
    6. Valenti R,
    7. Parodi G,
    8. Neumann FJ,
    9. Colombo A,
    10. Antoniucci D,
    11. JETSTENT Trial Investigators
    . Comparison of AngioJet rheolytic thrombectomy before direct infarct artery stenting with direct stenting alone in patients with acute myocardial infarction. The JETSTENT trial. J Am Coll Cardiol. 2010;56:1298–1306. doi: 10.1016/j.jacc.2010.06.011.
    OpenUrlCrossRefPubMed
  219. 219.↵
    1. Ciszewski M,
    2. Pregowski J,
    3. Teresińska A,
    4. Karcz M,
    5. Kalińczuk Ł,
    6. Pracon R,
    7. Witkowski A,
    8. Rużyłło W.
    Aspiration coronary thrombectomy for acute myocardial infarction increases myocardial salvage: single center randomized study. Catheter Cardiovasc Interv. 2011;78:523–531. doi: 10.1002/ccd.22933.
    OpenUrlCrossRefPubMed
  220. 220.↵
    1. De Carlo M,
    2. Aquaro GD,
    3. Palmieri C,
    4. Guerra E,
    5. Misuraca L,
    6. Giannini C,
    7. Lombardi M,
    8. Berti S,
    9. Petronio AS.
    A prospective randomized trial of thrombectomy versus no thrombectomy in patients with ST-segment elevation myocardial infarction and thrombus-rich lesions: MUSTELA (MUltidevice Thrombectomy in Acute ST-Segment ELevation Acute Myocardial Infarction) trial. JACC Cardiovasc Interv. 2012;5:1223–1230. doi: 10.1016/j.jcin.2012.08.013.
    OpenUrlCrossRefPubMed
  221. 221.↵
    1. Stone GW,
    2. Maehara A,
    3. Witzenbichler B,
    4. et al.,
    5. INFUSE-AMI Investigators
    . Intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocardial infarction: the INFUSE-AMI randomized trial. JAMA. 2012;307:1817–1826. doi: 10.1001/jama.2012.421.
    OpenUrlCrossRefPubMed
  222. 222.↵
    1. Patel MR,
    2. Smalling RW,
    3. Thiele H,
    4. Barnhart HX,
    5. Zhou Y,
    6. Chandra P,
    7. Chew D,
    8. Cohen M,
    9. French J,
    10. Perera D,
    11. Ohman EM.
    Intra-aortic balloon counterpulsation and infarct size in patients with acute anterior myocardial infarction without shock: the CRISP AMI randomized trial. JAMA. 2011;306:1329–1337. doi: 10.1001/jama.2011.1280.
    OpenUrlCrossRefPubMed
  223. 223.↵
    1. Piot C,
    2. Croisille P,
    3. Staat P,
    4. et al
    . Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med. 2008;359:473–481. doi: 10.1056/NEJMoa071142.
    OpenUrlCrossRefPubMed
  224. 224.↵
    1. Ghaffari S,
    2. Kazemi B,
    3. Toluey M,
    4. Sepehrvand N.
    The effect of prethrombolytic cyclosporine-A injection on clinical outcome of acute anterior ST-elevation myocardial infarction. Cardiovasc Ther. 2013;31:e34–e39. doi: 10.1111/1755-5922.12010.
    OpenUrlCrossRefPubMed
  225. 225.↵
    1. Cung TT,
    2. Morel O,
    3. Cayla G,
    4. et al
    . Cyclosporine before PCI in patients with acute myocardial infarction. N Engl J Med. 2015;373:1021–1031. doi: 10.1056/NEJMoa1505489.
    OpenUrlCrossRefPubMed
  226. 226.↵
    1. Ottani F,
    2. Latini R,
    3. Staszewsky L,
    4. et al.,
    5. CYCLE Investigators
    . Cyclosporine A in reperfused myocardial infarction: the multicenter, controlled, open-label CYCLE trial. J Am Coll Cardiol. 2016;67:365–374. doi: 10.1016/j.jacc.2015.10.081.
    OpenUrlPubMed
  227. 227.↵
    1. Heusch G.
    CIRCUS: a kiss of death for cardioprotection? Cardiovasc Res. 2015;108:215–216. doi: 10.1093/cvr/cvv225.
    OpenUrlFREE Full Text
  228. 228.↵
    1. Thiele H,
    2. Schindler K,
    3. Friedenberger J,
    4. Eitel I,
    5. Fürnau G,
    6. Grebe E,
    7. Erbs S,
    8. Linke A,
    9. Möbius-Winkler S,
    10. Kivelitz D,
    11. Schuler G.
    Intracoronary compared with intravenous bolus abciximab application in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: the randomized Leipzig immediate percutaneous coronary intervention abciximab IV versus IC in ST-elevation myocardial infarction trial. Circulation. 2008;118:49–57. doi: 10.1161/CIRCULATIONAHA.107.747642.
    OpenUrlAbstract/FREE Full Text
  229. 229.↵
    1. Marzilli M,
    2. Orsini E,
    3. Marraccini P,
    4. Testa R.
    Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction. Circulation. 2000;101:2154–2159.
    OpenUrlAbstract/FREE Full Text
  230. 230.↵
    1. Niccoli G,
    2. Rigattieri S,
    3. De Vita MR,
    4. et al
    . Open-label, randomized, placebo-controlled evaluation of intracoronary adenosine or nitroprusside after thrombus aspiration during primary percutaneous coronary intervention for the prevention of microvascular obstruction in acute myocardial infarction: the REOPEN-AMI study (Intracoronary Nitroprusside Versus Adenosine in Acute Myocardial Infarction). JACC Cardiovasc Interv. 2013;6:580–589. doi: 10.1016/j.jcin.2013.02.009.
    OpenUrlCrossRefPubMed
  231. 231.↵
    1. Fokkema ML,
    2. Vlaar PJ,
    3. Vogelzang M,
    4. Gu YL,
    5. Kampinga MA,
    6. de Smet BJ,
    7. Jessurun GA,
    8. Anthonio RL,
    9. van den Heuvel AF,
    10. Tan ES,
    11. Zijlstra F.
    Effect of high-dose intracoronary adenosine administration during primary percutaneous coronary intervention in acute myocardial infarction: a randomized controlled trial. Circ Cardiovasc Interv. 2009;2:323–329. doi: 10.1161/CIRCINTERVENTIONS.109.858977.109.858977.
    OpenUrlAbstract/FREE Full Text
  232. 232.↵
    1. Garcia-Dorado D,
    2. García-del-Blanco B,
    3. Otaegui I,
    4. Rodríguez-Palomares J,
    5. Pineda V,
    6. Gimeno F,
    7. Ruiz-Salmerón R,
    8. Elizaga J,
    9. Evangelista A,
    10. Fernandez-Avilés F,
    11. San-Román A,
    12. Ferreira-González I.
    Intracoronary injection of adenosine before reperfusion in patients with ST-segment elevation myocardial infarction: a randomized controlled clinical trial. Int J Cardiol. 2014;177:935–941. doi: 10.1016/j.ijcard.2014.09.203.
    OpenUrlCrossRefPubMed
  233. 233.↵
    1. Siddiqi N,
    2. Neil C,
    3. Bruce M,
    4. et al.,
    5. NIAMI investigators
    . Intravenous sodium nitrite in acute ST-elevation myocardial infarction: a randomized controlled trial (NIAMI). Eur Heart J. 2014;35:1255–1262. doi: 10.1093/eurheartj/ehu096.
    OpenUrlAbstract/FREE Full Text
  234. 234.↵
    1. Jones DA,
    2. Pellaton C,
    3. Velmurugan S,
    4. Rathod KS,
    5. Andiapen M,
    6. Antoniou S,
    7. van Eijl S,
    8. Webb AJ,
    9. Westwood MA,
    10. Parmar MK,
    11. Mathur A,
    12. Ahluwalia A.
    Randomized phase 2 trial of intracoronary nitrite during acute myocardial infarction. Circ Res. 2015;116:437–447. doi: 10.1161/CIRCRESAHA.116.305082.
    OpenUrlAbstract/FREE Full Text
  235. 235.↵
    1. Ott I,
    2. Schulz S,
    3. Mehilli J,
    4. Fichtner S,
    5. Hadamitzky M,
    6. Hoppe K,
    7. Ibrahim T,
    8. Martinoff S,
    9. Massberg S,
    10. Laugwitz KL,
    11. Dirschinger J,
    12. Schwaiger M,
    13. Kastrati A,
    14. Schmig A,
    15. REVIVAL-3 Study Investigators
    . Erythropoietin in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a randomized, double-blind trial. Circ Cardiovasc Interv. 2010;3:408–413. doi: 10.1161/CIRCINTERVENTIONS.109.904425.
    OpenUrlAbstract/FREE Full Text
  236. 236.↵
    1. Atar D,
    2. Arheden H,
    3. Berdeaux A,
    4. et al
    . Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: MITOCARE study results. Eur Heart J. 2015;36:112–119. doi: 10.1093/eurheartj/ehu331.
    OpenUrlAbstract/FREE Full Text
  237. 237.↵
    1. Gibson CM,
    2. Giugliano RP,
    3. Kloner RA,
    4. et al
    . EMBRACE STEMI study: a Phase 2a trial to evaluate the safety, tolerability, and efficacy of intravenous MTP-131 on reperfusion injury in patients undergoing primary percutaneous coronary intervention. Eur Heart J. 2015;10.1093/eurheartj/ehv597
  238. 238.↵
    1. Kitakaze M,
    2. Asakura M,
    3. Kim J,
    4. et al.,
    5. J-WIND investigators
    . Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials. Lancet. 2007;370:1483–1493. doi: 10.1016/S0140-6736(07)61634-1.
    OpenUrlCrossRefPubMed
  239. 239.↵
    1. Er F,
    2. Dahlem KM,
    3. Nia AM,
    4. et al
    . Randomized control of sympathetic drive with continuous intravenous esmolol in patients with acute ST-segment elevation myocardial infarction: The BEtA-Blocker Therapy in Acute Myocardial Infarction (BEAT-AMI) trial. JACC Cardiovasc Interv. 2016;9:231–240. doi: 10.1016/j.jcin.2015.10.035.
    OpenUrlCrossRefPubMed
  240. 240.↵
    1. Lønborg J,
    2. Kelbæk H,
    3. Vejlstrup N,
    4. Bøtker HE,
    5. Kim WY,
    6. Holmvang L,
    7. Jørgensen E,
    8. Helqvist S,
    9. Saunamäki K,
    10. Terkelsen CJ,
    11. Schoos MM,
    12. Køber L,
    13. Clemmensen P,
    14. Treiman M,
    15. Engstrøm T.
    Exenatide reduces final infarct size in patients with ST-segment-elevation myocardial infarction and short-duration of ischemia. Circ Cardiovasc Interv. 2012;5:288–295. doi: 10.1161/CIRCINTERVENTIONS.112.968388.
    OpenUrlAbstract/FREE Full Text
  241. 241.↵
    1. Lønborg J,
    2. Vejlstrup N,
    3. Kelbæk H,
    4. et al
    . Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J. 2012;33:1491–1499. doi: 10.1093/eurheartj/ehr309.
    OpenUrlAbstract/FREE Full Text
  242. 242.↵
    1. Woo JS,
    2. Kim W,
    3. Ha SJ,
    4. Kim JB,
    5. Kim SJ,
    6. Kim WS,
    7. Seon HJ,
    8. Kim KS.
    Cardioprotective effects of exenatide in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of exenatide myocardial protection in revascularization study. Arterioscler Thromb Vasc Biol. 2013;33:2252–2260. doi: 10.1161/ATVBAHA.113.301586.
    OpenUrlAbstract/FREE Full Text
  243. 243.↵
    1. Reffelmann T,
    2. Hale SL,
    3. Li G,
    4. Kloner RA.
    Relationship between no reflow and infarct size as influenced by the duration of ischemia and reperfusion. Am J Physiol Heart Circ Physiol. 2002;282:H766–H772. doi: 10.1152/ajpheart.00767.2001.
    OpenUrlAbstract/FREE Full Text
  244. 244.↵
    1. Reffelmann T,
    2. Kloner RA.
    Microvascular reperfusion injury: rapid expansion of anatomic no reflow during reperfusion in the rabbit. Am J Physiol Heart Circ Physiol. 2002;283:H1099–H1107. doi: 10.1152/ajpheart.00270.2002.
    OpenUrlAbstract/FREE Full Text
  245. 245.↵
    1. Reffelmann T,
    2. Kloner RA.
    Is microvascular protection by cariporide and ischemic preconditioning causally linked to myocardial salvage? Am J Physiol Heart Circ Physiol. 2003;284:H1134–H1141. doi: 10.1152/ajpheart.00563.2002.
    OpenUrlAbstract/FREE Full Text
  246. 246.↵
    1. Heusch G,
    2. Kleinbongard P,
    3. Skyschally A.
    Myocardial infarction and coronary microvascular obstruction: an intimate, but complicated relationship. Basic Res Cardiol. 2013;108:380. doi: 10.1007/s00395-013-0380-y.
    OpenUrlCrossRefPubMed
  247. 247.↵
    1. Kloner RA,
    2. Rude RE,
    3. Carlson N,
    4. Maroko PR,
    5. DeBoer LW,
    6. Braunwald E.
    Ultrastructural evidence of microvascular damage and myocardial cell injury after coronary artery occlusion: which comes first? Circulation. 1980;62:945–952.
    OpenUrlAbstract/FREE Full Text
  248. 248.↵
    1. Sanz E,
    2. García Dorado D,
    3. Oliveras J,
    4. Barrabés JA,
    5. Gonzalez MA,
    6. Ruiz-Meana M,
    7. Solares J,
    8. Carreras MJ,
    9. García-Lafuente A,
    10. Desco M.
    Dissociation between anti-infarct effect and anti-edema effect of ischemic preconditioning. Am J Physiol. 1995;268:H233–H241.
    OpenUrl
  249. 249.↵
    1. Hori M,
    2. Gotoh K,
    3. Kitakaze M,
    4. Iwai K,
    5. Iwakura K,
    6. Sato H,
    7. Koretsune Y,
    8. Inoue M,
    9. Kitabatake A,
    10. Kamada T.
    Role of oxygen-derived free radicals in myocardial edema and ischemia in coronary microvascular embolization. Circulation. 1991;84:828–840.
    OpenUrlAbstract/FREE Full Text
  250. 250.↵
    1. Guarini G,
    2. Kiyooka T,
    3. Ohanyan V,
    4. et al
    . Impaired coronary metabolic dilation in the metabolic syndrome is linked to mitochondrial dysfunction and mitochondrial DNA damage. Basic Res Cardiol. 2016;111:29. doi: 10.1007/s00395-016-0547-4.
    OpenUrlCrossRefPubMed
View Abstract
Back to top
Previous ArticleNext Article

This Issue

Circulation Research
May 13, 2016, Volume 118, Issue 10
  • Table of Contents
Previous ArticleNext Article

Jump to

  • Article
    • Abstract
    • Coronary Circulation as a Determinant of Myocardial Ischemic Injury
    • Coronary Circulation as a Determinant of Reperfusion and Reperfusion Injury
    • Manifestations of Myocardial Ischemia/Reperfusion Injury in the Coronary Circulation
    • Coronary Vascular Protection by Ischemic Preconditioning
    • Coronary Vascular Protection by Ischemic Postconditioning
    • Coronary Vascular Protection by Remote Ischemic Conditioning
    • Coronary Vascular Protection by Drugs and Cardioprotective Interventions
    • Coronary Microvascular Injury: Cause or Consequence of Myocardial Ischemia/Reperfusion
    • Sources of Funding
    • Disclosures
    • Footnotes
    • References
  • Figures & Tables
  • Info & Metrics

Article Tools

  • Print
  • Citation Tools
    The Coronary Circulation as a Target of Cardioprotection
    Gerd Heusch
    Circulation Research. 2016;118:1643-1658, originally published May 12, 2016
    https://doi.org/10.1161/CIRCRESAHA.116.308640

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
  •  Download Powerpoint
  • Article Alerts
    Log in to Email Alerts with your email address.
  • Save to my folders

Share this Article

  • Email

    Thank you for your interest in spreading the word on Circulation Research.

    NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

    Enter multiple addresses on separate lines or separate them with commas.
    The Coronary Circulation as a Target of Cardioprotection
    (Your Name) has sent you a message from Circulation Research
    (Your Name) thought you would like to see the Circulation Research web site.
  • Share on Social Media
    The Coronary Circulation as a Target of Cardioprotection
    Gerd Heusch
    Circulation Research. 2016;118:1643-1658, originally published May 12, 2016
    https://doi.org/10.1161/CIRCRESAHA.116.308640
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Related Articles

Cited By...

Subjects

  • Basic, Translational, and Clinical Research
    • Ischemia
    • Coronary Circulation

Circulation Research

  • About Circulation Research
  • Editorial Board
  • Instructions for Authors