ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Ann Thorac Surg 2009;87:164-171. doi:10.1016/j.athoracsur.2008.08.016
© 2009 The Society of Thoracic Surgeons
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Shinji Miyamoto
Joseph H. Gorman, III
Robert C. Gorman
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hamamoto, H.
Right arrow Articles by Gorman, R. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hamamoto, H.
Right arrow Articles by Gorman, R. C.
Related Collections
Right arrow Myocardial protection
Right arrowRelated Articles

Original Articles: Adult Cardiac

Regional Heterogeneity of Myocardial Reperfusion Injury: Effect of Mild Hypothermia

Hirotsugu Hamamoto, MDa,b, Bradley G. Leshnower, MDa, Landi M. Parish, MDa, Hiroaki Sakamoto, MDa, Shinya Kanemoto, MDa, Robin Hinmon, MSa, Shinji Miyamoto, MD, PhDb, Joseph H. Gorman, III, MDa, Robert C. Gorman, MDa,*

a Harrison Department of Surgical Research, Glenolden Research Laboratory, University of Pennsylvania, Glenolden, Pennsylvania
b Department of Cardiovascular Surgery, Faculty of Medicine, Oita University, Oita, Japan

Accepted for publication August 7, 2008.

* Address correspondence to Dr Robert C. Gorman, Gorman Cardiovascular Research Group, Glenolden Research Laboratory, University of Pennsylvania, 500 S. Ridgeway Avenue, Glenolden, PA 19036 (Email: gormanr{at}uphs.upenn.edu).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Footnotes
 Acknowledgments
 References
 
Background: Mild hypothermia confers a myocardial protective effect that may make it a useful adjunct to reperfusion therapy for myocardial infarction (MI). The effect of temperature on the extent and distribution of myocardial reperfusion injury in a collateral deficient ovine model was studied.

Methods: Topical cooling maintained left atrial temperature at 39.5°C (n = 8), 38.5°C (n = 5), 37.5°C (n = 6), 36.5°C (n = 6), or 35.5°C (n = 5) in sheep prior to 1 hour of coronary occlusion to produce an anteroapical myocardial risk area (AR) followed by 3 hours of reperfusion. A dual staining and planimetry technique was used to assess infarct size as a percentage of the AR in 3 myocardial short axis slices that included the entire AR (slice 1= most apical; slice 3= most basal). The subendocardial, midmyocardial, and subepicardial extent in short axis of the infarct was also assessed in each slice. Microspheres assessed transmural blood flow.

Results: At 39.5°C there was a long-axis gradient in myocardial injury that was most severe at the apex and lessened toward the base. The midmyocardial region was most susceptible to injury at all long axis levels. Temperature reduction (as little as 1°C) was associated with improved salvage that was most pronounced in the apical subendocardium and least in the basilar midmyocardium. Reperfusion at 39.5°C resulted in severe transmural microvascular injury (no-reflow) that was completely obviated at temperatures below 38.5°C.

Conclusions: Myocardial reperfusion injury varies over the long and short LV axes. Mild hypothermia preferentially improves myocardial salvage at the LV apex. Small temperature changes can dramatically affect microvascular integrity.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Footnotes
 Acknowledgments
 References
 
The myocardial response to reperfusion injury has been studied extensively since the seminal works of Reimer and colleagues [1] and Reimer and Jennings [2] were published three decades ago. Using a canine model, with its well-developed native system of functional, preformed epicardial collaterals, these investigators described a transmural "wavefront" progression of myocardial cell death extending from the subendocardium toward the subepicardium with increasing lengths of ischemia.

Recently, it has been demonstrated that the progression of ischemic myocardial cell death does not occur in a wavefront fashion in animals that are devoid of a significant coronary collateral circulation (sheep and pigs) [3, 4]. In these preparations the midmyocardial region was demonstrated to be more susceptible to reperfusion injury than either the subendocardium or subepicardium. These data suggest that the anatomy of the coronary collateral circulation is the primary determinant of transmural infarct distribution after myocardial ischemia and reperfusion [3]. The coronary collateral circulation in patients with coronary artery disease (CAD) has been demonstrated to be highly variable [5]. It is likely that collateral deficient hearts provide an accurate representation of the coronary anatomy found in a substantial subset of patients with CAD. Patients without well-developed coronary collaterals are likely those who suffer myocardial infarction (MI) without prior symptoms of ischemia [6].

Essentially all of the existing data regarding the spatial distribution of myocardial reperfusion injury have resulted from studies that assessed the transmural extent of the injury. Little information exists regarding how, or if, the extent of injury varies from apex to base on the left ventricular (LV) wall. One of the goals of the current experiment was to describe the regional variability of myocardial reperfusion injury from apex to base in addition to its transmural distribution.

The other goal of this study was to determine how mild hypothermia affects the regional distribution of myocardial reperfusion injury. A growing body of preclinical [7–10] and clinical data [11–13] suggests that mild reductions in body temperature (<4°C) during ischemia can have significant cardioprotective effects. Interestingly, two recent clinical studies have found that patients with apical infarcts benefit most from the institution of mild systemic hypothermia prior to reperfusion [12, 13]. We hypothesized that this finding was due to regional myocardial variability within the LV in response to hypothermia during ischemia and subsequent reperfusion. A sheep model of anteroapical infarction was used to test this hypothesis.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Footnotes
 Acknowledgments
 References
 
Temperature Management
After the induction of anesthesia, sheep were sheared of all wool from neck to rump. Cooling-warming pads from the topical hyperthermia-hypothermia unit (Medi-Therm III, Gaymar Industries Inc, Orchard Park, NY) were set up on both sides of the animal and the temperature of the device was set to the goal temperature. Ice bags were put on the neck, axillary, and inguinal regions. If the temperature went down under the maintenance range a halogen warming light was used to increase temperature and the temperature setting on the hyperthermia-hypothermia unit was adjusted. For each experiment the same dedicated technician was assigned to manage the animal's temperature.

Rectal and left atrial (LA) temperatures were monitored continually throughout the experiment and recorded at 15-minute intervals. Rectal and LA temperature measurements were always within 0.3°C. The LA temperature was used to determine when ischemia would be induced.

Surgical Protocol
Thirty-one male sheep weighing 35 to 40 kg were used in this study. Animals were treated under experimental protocols approved by the University of Pennsylvania's Institutional Animal Care and Use Committee (IACUC) and in compliance with the Guide for the Care and Use of Laboratory Animals (National Institute of Health Publication No. 85-23 as revised in 1996).

Anesthesia was induced with thiopental sodium (10 to 15 mg/kg intravenously), and sheep were intubated, anesthetized with isoflurane (1.5 to 2%), and ventilated with oxygen. Catheters were placed in a femoral artery and internal jugular vein for the continuous measurement of blood pressure and the administration of intravenous medications. A Swan-Ganz catheter (Baxter Healthcare Corp, Irvine, CA) was introduced into the pulmonary artery through the internal jugular vein. Animals underwent a left thoracotomy and silicone vascular loops (Quest Medical Inc, Allen, TX) were placed around the left anterior descending artery (LAD) and its second diagonal branch 40% of the distance from the apex to the base of the heart to allow atraumatic occlusion of these arteries. Occlusion of these arteries at these locations has produced a well-characterized model of anteroapical myocardial infarction in our laboratory [14]. After tightening the snares, ischemia was confirmed by a visible color change in the ischemic myocardial region and ST segment elevations on the electrocardiogram (ECG). At the end of the 1 hour ischemic period, coronary snares were loosened and the previously ischemic myocardium was reperfused for 3 hours in all animals.

Arterial blood pressure, heart rate, and ECG were continuously monitored (HP 78534C; Hewlett Packard, Palo Alto, CA) throughout the protocol in all animals. These parameters, as well as central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), and cardiac output (CO) were recorded at 30-minute intervals. Temperature was maintained at the following values prior to the induction of ischemia and throughout the remainder of the experiment: 39.5°C (n = 38.5°C (n = 5); 37.5°C (n = 6); 36.5°C (n = 6); and 35.5°C (n = 5). The normal body temperature range for nonfasting, nonpregnant sheep is 39°C to 40.5°C [15].

Analysis of Area at Risk and Infarct Size
At the completion of the protocol, the coronary snares were retightened, vascular clamps were used to occlude the aorta, pulmonary artery, and inferior vena cava, and the right atrium was incised. Evans blue dye (1 mL/kg; Sigma, St. Louis, MO) was injected through the left atrium to delineate the ischemic myocardial risk area (AR). All animals were euthanized by an injection of potassium chloride into the left atrium. The heart was excised and the LV was sectioned perpendicular to its long axis into 6 slices (Fig 1). The slices were then numbered from 1 to 6 with 1 being the most apical slice and 6 being the most basilar. The vast majority of the area at risk was always contained within slices 1, 2, and 3. Infarct area was delineated by photographing and measuring the slices after 20 minutes of incubation in 2% triphenyltetrazolium chloride at 37°C. The thickness of each slice was measured with a digital micrometer and all slices were photographed. All photographs were imported into an image analysis program (Image-Pro Plus; MediaCybernetics, Silver Spring, MD), and computerized planimetry was performed to determine the overall size of the AR and infarct. The AR is expressed as a percentage of the LV, and the infarct size (I) is expressed as a percentage of the AR (I/AR).


Figure 1
View larger version (104K):
[in this window]
[in a new window]

  		Fig 1. Sheep left ventricular (LV) sections sliced perpendicular to its long axis after staining with Evans blue dye to delineate the risk area. Slice 1 is the most apical region. Slice 3 is most basilar, located approximately halfway between the apex and base of the LV.

 
Transmural Analysis of Infarct Distribution
As previously described, we employed a customized planimetry technique on the AR contained in slices 1, 2, and 3 to evaluate the extent of ischemic injury in the subendocardium, midmyocardium, and subepicardium [3]. Briefly, after basic planimetry was completed on each slice, the transmural width of the LV wall was divided into three equivalent segments along multiple radii within the AR and individual circumferential arcs were created which connected these radially oriented points. These arcs were then connected circumferentially to form concentric ellipses, which divided the AR into three equivalent areas (subendocardium, midmyocardium, and subepicardium). Regional AR and regional I/AR were measured and calculated in each of the three areas of myocardium for each slice (Fig 2). Therefore, regional I/AR was calculated for nine myocardial regions (subendocardium, midmyocardium, and subepicardium in slices 1, 2, and 3) at five different temperatures.


Figure 2
View larger version (88K):
[in this window]
[in a new window]

  		Fig 2. Photographs with planimetry tracings of the ovine left ventricle sliced perpendicular to its long axis. (A) Evans blue dye staining to delineate the ischemic area at risk (AR). The AR is the unstained myocardium. (B) triphenyltetrazolium chloride (TTC) staining to delineate viable (brick red) from nonviable (pale) myocardium in the AR. (C) technique for transmural analysis. The AR is divided into equally sized subendocardium, midmyocardium, and subepicardium regions.

 
Regional Blood Flow Measurements
In all animals, fifteen million color-coded, 15.5-µm-diameter NuFlow fluorescent microspheres (IMT Laboratories, Irvine, CA) were injected to measure regional blood flow (RBF). Injections were made at baseline (prior to ischemia once goal temperature was achieved), after 30 minutes of ischemia, at 10 minutes after reperfusion, and after 180 minutes of reperfusion. Reference blood samples were taken at all time points. At the end of the experiment, in a similar fashion to the transmural I/AR analysis described above, the AR from slice 2 in each animal was isolated and circumferentially sectioned into three equivalent areas: subendocardium, midmyocardium, and subepicardium. These three areas of myocardium, as well as a transmural specimen and reference blood samples, were analyzed using flow cytometry for microsphere content by IMT Laboratories. Regional perfusion was calculated using the following formula: Qm = (Cm x Qr)/Cr, where Qm = myocardial blood flow per gram (mL/min/g) of sample, Cm = microsphere count per gram of tissue in sample, Qr = withdrawal rate of the reference blood sample (mL/min), and Cr = microsphere count in the reference blood sample. The RBF values were normalized and expressed as a percentage of baseline (preischemic) flow.

Statistical Analysis
Measurements are reported as means ± standard error of the mean. Analysis of variance (ANOVA) was used for all comparisons among groups, and repeated measures ANOVA was used for all comparisons within groups. Individual post hoc comparisons were performed using the Tukey "Honestly Significantly Different" test. All analyses were completed using SPSS version 11.0 (SPSS Inc, Chicago, IL). Statistically significant differences were established at a p value less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Footnotes
 Acknowledgments
 References
 
Temperature and Hemodynamics
Once goal temperature was achieved it was maintained with very little fluctuation throughout the course of the experiment in all groups (Fig 3). At baseline the hypothermic groups experienced a small but significant reduction in heart rate. This difference did not persist after the initiation of ischemia and subsequent reperfusion. After 180 minutes of reperfusion the hypothermic groups demonstrated a statistically significant, but small, reduction in CVP and PCWP. No other parameters were significantly influenced by temperature. All hemodynamic data are presented in Table 1.


Figure 3
View larger version (19K):
[in this window]
[in a new window]

  		Fig 3. Left atrial temperature for each group of animals over time for the entire duration of the experiment. Temperature was maintained very close to goal values for all animals in all groups.

 

View this table:
[in this window]
[in a new window]

  		Table 1 Hemodynamic Data
 
Infarct Distribution: Normothermia
The AR did not vary significantly between temperature groups and averaged 24.1 ± 3.2% of the LV mass. At normothermia (39.5°C) total I/AR (for each slice) varied significantly between slice 1 (89.6 ± 1.9%), slice 2 (83.6 ± 1.9%), and slice 3 (70.7 ± 3.5%). In all slices the extent of the injury was least severe in the subendocardial region and most severe in the midmyocardial region. At normothermia, regional I/AR varied widely between myocardial regions: the apical (slice 1) midmyocardial region was most susceptible to injury (I/AR = 97.1 ± 1.2%), with the endocardium in the most basilar region (slice 3) being least prone to injury (I/AR = 64.8 ± 4.5%; Table 2).


View this table:
[in this window]
[in a new window]

  		Table 2 Infarct Size (I) as a Percentage of the Area at Risk (AR) for Each Entire Slice (Slice 1 = Apical, Slice 3 = Basilar) as Well as for the Endocardial, Midmyocardial, and Epicardial Regions of Each Slice
 
Infarct Distribution: Effect of Temperature
The total I/AR in slices 1, 2, and 3 were progressively reduced with increasing reductions in temperature; these differences reached statistical significance relative to normothermia at 37.5°C and below in all slices. Slice 1 (most apical) demonstrated a greater response to hypothermia at all temperatures compared with either slice 2 or slice 3. This difference was most pronounced at 35.5°C, where I/AR was 3.6 ± 1.1%, 21.5 ± 7.9%, and 30.1 ± 4.4% for slices 1, 2, and 3, respectively (Fig 4).


Figure 4
View larger version (33K):
[in this window]
[in a new window]

  		Fig 4. Infarct size as a percentage of the myocardial area at risk (I/AR) for each left ventricular slice at varying levels of hypothermia. (ap < 0.05 vs 39.5°C; bp < 0.05 vs 38.5°C; cp < 0.05 vs 37.5°C; dp < 0.05 vs 36.5°C; ep < 0.05 vs slice 1; fp < 0.05 vs Slice 2.

 
In all slices and at all temperature reductions, the subendocardial region consistently benefited most from hypothermia followed by the subepicardium. The midmyocardium derived the least benefit from temperature reduction. Changes in subendocardial I/AR reached statistical significance relative to normothermia at 38.5°C in slices 1 and 2. The subendocardial response to a 1°C reduction in temperature was most dramatic in slice 1, where subendocardial I/AR was 77.0 ± 4.5% at 39.5°C and 28.2 ± 5.7% at 38.5°C (p < 0.05). All myocardial salvage data are presented in Table 2.

Regional Blood Flow
Normalized RBF data for the subendocardium, midmyocardium, subepicardium, and transmural specimens from slice 2 are summarized in Table 3. Coronary occlusion resulted in profound transmural ischemia. Reperfusion was associated with an initial hyperemic response that varied from a 1.5-fold to 2.5-fold increase in baseline RBF values 10 minutes after reperfusion. This early increase in RBF was apparent in the subendocardial, midmyocardial, epicardial, and transmural specimens at all temperatures. At normothermia a no-reflow phenomenon [16] became apparent at 180 minutes after reperfusion with total transmural blood flow falling to 29.4 ± 4.5% of its baseline, preischemic value. This normothermic no-reflow phenomenon was most severe in the endocardial and midmyocardial regions. Any degree of hypothermia was found to ameliorate the normothermic no-reflow phenomenon, with temperatures of 37.5°C or less resulting in transmural blood flow values similar to preischemic levels (Fig 5).


View this table:
[in this window]
[in a new window]

  		Table 3 Normalized Regional Blood Flow (RBF) for a Transmural Section Through the Area at Risk of Slice 2 as Well as for the Endocardial, Midmyocardial and Epicardial Regions of Slice 2
 

Figure 5
View larger version (27K):
[in this window]
[in a new window]

  		Fig 5. Normalized blood flow in a transmural region of myocardium within the area at risk of slice 2 at varying levels of hypothermia. Data are presented as a percentage of baseline pre-ischemic blood flow. (ap < 0.05 vs 39.5°C; bp < 0.05 vs ischemia; cp < 0.05 vs reperfusion (10 minutes).

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Footnotes
 Acknowledgments
 References
 
The transmural progression of myocardial necrosis with increasing ischemic durations followed by reperfusion were described in the canine model, with its extensive native system of functional, preformed epicardial collaterals, by Reimer and colleagues [1] and Reimer and Jennings [2]. These investigators described a transmural wavefront of myocardial necrosis extending from the subendocardium toward the subepicardium with increasing lengths of ischemia. Our group has recently demonstrated that in collateral deficient species such as sheep [3] and rabbits (unpublished data) that the midmyocardium is the region that is most susceptible to reperfusion injury. These data suggest that the progression of transmural ischemic injury is dependent on the development and distribution of the collateral coronary circulation, and that the canine and ovine coronary circulations effectively model two distinct subsets of patients with CAD. Patients without well-developed coronary collaterals are likely those who suffer myocardial infarction (MI) secondary to rupture of an unstable plaque without prior symptoms of ischemia. These patients would be best modeled by the collaterally deficient ovine heart. Patients with long standing symptoms of chronic ischemia would be more likely to develop coronary collaterals and therefore be best modeled by the collateral rich canine heart.

In this experiment we expand on our previous work, which only examined the transmural distribution of myocardial injury in the collateral limited ovine model of myocardial ischemia-reperfusion injury at normothermia. In the current study, at normal body temperature we demonstrated a long-axis gradient in myocardial injury that was most severe at the LV apex and lessened towards the base of the heart. When the transmural extent of the injury was also considered we showed that the more basilar endocardial regions were most resistant to ischemic injury, while the apical midmyocardium was the region most susceptible. The explanation for these regional differences at normothermia is unclear but may be related to regional mechanical stresses that reach maximum levels at the infarcted LV apex [17].

The current study adds to a growing body of preclinical and clinical data that support the use of mild hypothermia as an adjunct to reperfusion therapy for acute MI [7–13]. Our data show that reductions in temperature as small as 1°C can significantly improve regional myocardial salvage and that increasing beneficial effects accrue with temperature reductions to 4°C. With each 1°C reduction in temperature from 39.5 to 36.5, regional myocardial salvage improved. However, the transmural distribution of myocardial injury remained the same; injury was always greatest in the midmyocardium and least in the subendocardium, thus confirming our previous work [3]. Our data also demonstrate that the salutary effect of mild hypothermia on ischemia-reperfusion induced myocardial injury varies significantly between myocardial regions along the long axis of the LV. We found that the subendocardial regions near the apex experienced dramatic reductions in infarct size (77% to 28%) when temperature was reduced only 1°C, from 39.5°C to 38.5°C. When temperature was reduced from 39.5°C to 35.5°C, myocardial injury was virtually eliminated in the most apical specimen (slice 1). The midmyocardial segments of the more basilar regions (slices 2 and 3) demonstrated the least benefit from hypothermia. Statistically significant reductions in infarct size only occurred in these regions at a temperature of 35.5°C. The absolute reduction in infarct size was also much smaller in these regions.

At normothermia, regional blood flow data were consistent with a significant transmural no-reflow phenomenon by 180 minutes after reperfusion, which was most severe in the subendocardium and midmyocardium. Transmural blood flow was greatly improved with only a 1°C reduction in core temperature and was essentially normalized at temperatures of 37.5°C or below. Previous investigators [18] have demonstrated the benefits of hypothermia in ameliorating the no-reflow phenomenon in small animal models. However, salutary effects of very subtle temperature changes in a large animal model have not been previously described.

Although this study was not designed to definitively determine the mechanism responsible for the regional variations in response to mild hypothermia described here, a potential hypothesis can be proposed. The myocardium that experienced the greatest myocardial salvage at the smallest temperature reductions were regions where the myocardium is thinnest (ie, apex) and where the myocardium is closest to the cooled blood pool contained in the LV cavity. It is possible that these parameters set up temperature gradients within the myocardium that were responsible for the described regional variations in myocardial salvage. In subsequent studies measurement of regional myocardial temperature will help to confirm the validity of this hypothesis.

Irrespective of their mechanism, the clinical implications of these findings are potentially important and may help to explain the results of early clinical trials and help to design future studies. In the Cooling as an Adjunctive Therapy to Percutaneous Intervention in Patients With Acute Myocardial Infarction trial, 395 patients with acute MI were assigned to undergo primary angioplasty with or without adjunctive hypothermia. Cooling was initiated before angioplasty (target temperature 33.0°C). Cooling was found to be safe and well-tolerated. However, the final infarct size at 30 days after angioplasty as measured by Tc-99 sestamibi single photon emission computed tomography imaging was similar in both study groups. A subgroup analysis demonstrated a significant reduction in infarct size in patients with apical infarctions [12]. Similar results were found in the multicenter ICE-IT trial [19, 20]. These clinical results are consistent with our experimental findings and suggest that subsequent clinical trials should focus on enrolling apically located infarctions.

The goal of this experiment was to assess the effect of varying degrees of mild hypothermia on the extent of myocardial injury associated with a standardized ischemia-reperfusion insult. While the results we report are interesting and have significant clinical implications, important questions remain to be studied. In this experiment we employed an anteroapical infarction that extended approximately half way up the anterior LV wall, and additional experiments will be required to determine if the long axis gradients in myocardial injury persist with infarcts that extend fully to the base of the heart. Ischemic durations beyond 1 hour were not studied. The effect of hypothermia on the pattern and extent of myocardial injury associated with more lengthy periods of ischemia will be important to understand. Temperature was maintained constant throughout the experiment; therefore, we were unable to evaluate at what time point during the ischemia-reperfusion interval that hypothermia was most crucial for optimizing myocardial salvage. Recent work in our laboratory using a rabbit model strongly suggests that the temperature at the time of reperfusion is most strongly associated with myocardial salvage [21]. Blood flow was only assessed in slice 2. It is likely that RBF varied over the long axis, as did myocardial salvage. We plan to study this phenomenon in future experiments.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Footnotes
 Acknowledgments
References
 
This study was supported by the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda MD (HL63954, HL71137 and HL76560). Robert Gorman and Joseph Gorman are supported by individual Established Investigator Awards from the American Heart Association.


   Footnotes
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Footnotes
Acknowledgments
 References
 
For related articles, see pages 8, 157 and 172


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Footnotes
 Acknowledgments
 References
 

  1. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wave front phenomenon of ischemic cell death. Myocardial infarct size vs. duration of coronary occlusion in dogs. Circulation 1977;56:786-794.[Abstract/Free Full Text]
  2. Reimer KA, 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.[Medline]
  3. Leshnower BG, Sakamoto H, Hamamoto H, Zeeshan A, Gorman III JH, Gorman RC. The progression of myocardial injury during coronary occlusion in the collateral deficient heart: a non-wavefront phenomenon Am J Physiol Heart Circ Physiol 2007;293:H1799-H1804.[Abstract/Free Full Text]
  4. Amado LC, Saliaris AP, Schuleri KH, et al. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction Proc Natl Acad Sci U S A 2005;102:11474-11479.[Abstract/Free Full Text]
  5. Pohl T, Seiler C, Billinger M, et al. Frequency distribution of collateral flow and factors influencing collateral channel development. Functional collateral channel measurement in 450 patients with coronary artery disease. J Am Coll Cardiol 2001;38:1872-1878.[Abstract/Free Full Text]
  6. Ambrose JA, Tannenbaum MA, Alexopoulos D, et al. Angiographic progression of coronary artery disease and the development of myocardial infarction J Am Coll Cardiol 1988;12:56-62.[Abstract]
  7. Chien GL, Wolff RA, Davis RF, van Winkle DM. "Normothermic range" temperature affects myocardial infarct size Cardiovasc Res 1994;28:1014-1017.[Abstract/Free Full Text]
  8. Duncker DJ, Klassen CL, Ishibashi Y, Herrlinger SH, Pavek TJ, Bache RJ. Effect of temperature on myocardial infarction in swine Am J Physiol Heart Circ Physiol 1996;270:H1189-H1199.[Abstract/Free Full Text]
  9. Hale SL, Kloner RA. Myocardial temperature in acute myocardial infarction: protection with mild regional hypothermia Am J Physiol Heart Circ Physiol 1997;273:H220-H227.[Abstract/Free Full Text]
  10. Schwartz LM, Verbinski SG, Vander Heide RS, Reimer KA. Epicardial temperature is a major predictor of myocardial infarct size in dogs J Mol Cell Cardiol 1997;29:1577-1583.[Medline]
  11. Dixon SR, Whitbourn RJ, Dae MW, et al. 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.[Abstract/Free Full Text]
  12. O'Neill WW, on behalf of the COOL-MI Investigators. A prospective, randomized trial of mild systemic hypothermia during PCI treatment of ST elevation MI. Presented at the 15th Annual Transcatheter Cardiovascular Therapeutics Symposium, Washington, DC, Sept 15–19, 2003.
  13. Ly HQ, Denault A, Dupuis J, et al. A pilot study: the noninvasive surface cooling thermoregulatory system for mild hypothermia induction in acute myocardial infarction (the NICAMI Study) Am Heart J 2005;150:933.[Medline]
  14. Markovitz LJ, Savage EB, Ratcliffe MB, et al. Large animal model of left ventricular aneurysm Ann Thorac Surg 1989;48:838-845.[Abstract/Free Full Text]
  15. Mohr EG, Krzywanek H. Endogenous oscillator and regulatory mechanisms of body temperature in sheep Physiol Behav 1995;57:339-347.[Medline]
  16. Kloner RA, Ganote CE, Jennings RB. The ‘no-reflow' phenomenon after temporary coronary occlusion in dogs J Clin Invest 1974;54:1496-1508.[Medline]
  17. Jackson BM, Gorman III JH, Salgo IS, et al. Border zone geometry increases wall stress after myocardial infarction: contrast echocardiographic assessment Am J Physiol Heart Circ Physiol 2003;284:H475-H479.[Abstract/Free Full Text]
  18. Hale SL, Dae MW, Kloner RA. Hypothermia during reperfusion limits ‘no-reflow' injury in a rabbit model of acute myocardial infarction Cardiovasc Res 2003;59:715-722.[Abstract/Free Full Text]
  19. Grines CL, on behalf of the ICE-IT Investigators. Intravascular cooling adjunctive to percutaneous coronary intervention for acute myocardial infarction. Presented at the 16th Annual Transcatheter Cardiovascular Therapeutics, Washington DC, Sept 27–Oct 1, 2004.
  20. Dixon SR. Infarct angioplasty: beyond stents and glycoprotein IIb/IIIa inhibitors Heart 2005;91(suppl 3):iii2-iii6.[Free Full Text]
  21. Kanemoto S, Matsubara S, Noma M, et al. Mild hypothermia to limit myocardial ischemia-reperfusion injury: importance of timing Ann Thorac Surg 2009;87:157-163.[Abstract/Free Full Text]

Related Articles

Mild Hypothermia to Limit Myocardial Ischemia-Reperfusion Injury: Importance of Timing
Shinya Kanemoto, Muneaki Matsubara, Mio Noma, Bradley G. Leshnower, Landi M. Parish, Benjamin M. Jackson, Robin Hinmon, Hirotsugu Hamamoto, Joseph H. Gorman, III, and Robert C. Gorman
Ann. Thorac. Surg. 2009 87: 157-163. [Abstract] [Full Text] [PDF]

Very Mild Hypothermia During Ischemia and Reperfusion Improves Postinfarction Ventricular Remodeling
Hirotsugu Hamamoto, Hiroaki Sakamoto, Bradley G. Leshnower, Landi M. Parish, Shinya Kanemoto, Robin Hinmon, Theodore Plappert, Shinji Miyamoto, Martin G. St. John-Sutton, Joseph H. Gorman, III, and Robert C. Gorman
Ann. Thorac. Surg. 2009 87: 172-177. [Abstract] [Full Text] [PDF]

Myocardial Infarction Comes Into the Cold!
David J. Chambers
Ann. Thorac. Surg. 2009 87: 8-10. [Extract] [Full Text] [PDF]



This article has been cited by other articles:


Home page
 J Am Coll CardiolHome page
C. Delhaye, M. Mahmoudi, and R. Waksman
Hypothermia Therapy: Neurological and Cardiac Benefits
J. Am. Coll. Cardiol., January 17, 2012; 59(3): 197 - 210.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
R. Tissier, B. Ghaleh, M. V. Cohen, J. M. Downey, and A. Berdeaux
Myocardial protection with mild hypothermia
Cardiovasc Res, December 26, 2011; (2011) cvr315v2.
[Abstract] [Full Text] [PDF]

Home page
 J CARDIOVASC PHARMACOL THERHome page
S. L. Hale and R. A. Kloner
Mild Hypothermia as a Cardioprotective Approach for Acute Myocardial Infarction: Laboratory to Clinical Application
Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2011; 16(2): 131 - 139.
[Abstract] [PDF]

Home page
 Ann. Thorac. Surg.Home page
D. J. Chambers
Myocardial Infarction Comes Into the Cold!
Ann. Thorac. Surg., January 1, 2009; 87(1): 8 - 10.
[Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
H. Hamamoto, H. Sakamoto, B. G. Leshnower, L. M. Parish, S. Kanemoto, R. Hinmon, T. Plappert, S. Miyamoto, M. G. St. John-Sutton, J. H. Gorman III, et al.
Very Mild Hypothermia During Ischemia and Reperfusion Improves Postinfarction Ventricular Remodeling
Ann. Thorac. Surg., January 1, 2009; 87(1): 172 - 177.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Shinji Miyamoto
Joseph H. Gorman, III
Robert C. Gorman
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hamamoto, H.
Right arrow Articles by Gorman, R. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hamamoto, H.
Right arrow Articles by Gorman, R. C.
Related Collections
Right arrow Myocardial protection
Right arrowRelated Articles

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS