| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Ann Thorac Surg 2002;73:1229-1235
© 2002 The Society of Thoracic Surgeons
a Departments of Thoracic and Cardiovascular Surgery, University Medical School, Regensburg, Germany
b Pathology, University Medical School, Regensburg, Germany
c Internal Medicine II, University Medical School, Regensburg, Germany
Accepted for publication December 28, 2001.
* Address reprint requests to Dr Schmitt, Department of Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115 USA
e-mail: jschmitt{at}genetics.med.harvard.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
|---|
Methods. Myocardial samples were obtained from 11 patients undergoing elective coronary artery bypass grafting before (control) and after cardioplegic arrest and reperfusion. Specimens were examined for apoptosis by electron microscopy, in situ end-labeling of DNA fragments, and biochemically for mitochondrial cytochrome c release.
Results. Electron microscopy revealed condensation and margination of nuclear chromatin after surgery, as well as swelling and membrane rupture in mitochondria of single myocytes surrounded by healthy cells. TUNEL-positive cells were also found. Cytochrome c release, an initial step in apoptosis, revealed a 3.4 ± 0.4–fold increase during surgery (p < 0.0001). Furthermore, cytochrome c release from otherwise intact mitochondria showed a negative correlation with left ventricular function and a positive correlation with the duration of cardioplegic arrest and reperfusion (p < 0.05).
Conclusions. Our data demonstrate that programmed cell death is evident early after open heart surgery and correlates with declining cardiac contractility. We conclude that apoptosis may be an important mechanism in postoperative myocardial stunning.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
|---|
Apoptosis is an actively regulated process of cellular self-destruction, thereby distinct from necrosis. It encloses mitochondrial changes with characteristic release of substances promoting apoptosis like cytochrome c [1]. Downstream in the apoptotic program the caspase cascade is activated, followed by cytoskeletal alterations, chromatin condensation, and DNA fragmentation, culminating in cell death [2, 3].
Programmed cell death is increasingly recognized to participate in the pathophysiology of various cardiac diseases. Apoptosis contributes significantly to myocyte death in hibernating myocardium [4] and in myocardial infarction, particularly in the peri-infarct border zone [5], which is part of the ischemia/reperfusion complex [6]. Apoptosis occurs when the ischemic insult is delivered in doses milder than that required for necrosis [7]. Furthermore, apoptosis has been hypothesized to be involved in the progression of dilated cardiomyopathy, in that loss of myocytes promotes myocardial dysfunction, resulting in heart failure [8].
We found morphologic, histochemical, and biochemical evidence for early stages of myocyte apoptosis arising during the course of open heart surgery. Furthermore, cytochrome c release from mitochondria, an essential component of different apoptotic signaling cascades [9, 10], correlated well with declining left ventricular function and with the duration of cardioplegic arrest and reperfusion. Our findings suggest apoptosis as a molecular basis for myocardial stunning early after cardiac surgery. Targeting early events in the cascade of cell death may therefore have therapeutic potential.
|
Material and methods |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
|---|
Measurement of hemodynamics
After induction of anesthesia, a pulmonary artery catheter (Baxter, Deerfield, IL) was inserted into the right internal jugular vein and advanced to the pulmonary artery. Pulmonary artery pressures were monitored continuously to ensure correct catheter placement. Pulmonary capillary wedge pressure (PCWP), mean pulmonary artery pressure (PAPmean), and cardiac index (CI) were recorded before surgical incision and at the end of the surgical procedure after chest closure. Cardiac output was measured using conventional thermodilution technique with manual injection of 10 mL iced saline solution. The average of three measurements was calculated.
Histologic methods
For terminal deoxinucleotidyl transferase-dUTP-biotin nick-end labeling (TUNEL) of DNA fragments, tissue sections were fixed in 10% formalin and were incubated with 2% hydrogen peroxide for 5 minutes and then with deoxinucleotidyl transferase for 60 minutes. Digoxigenin-dUTP was visualized by an antidigoxigenin peroxidase conjugate and 3,3-diaminobenzidine. Nuclear counterstaining was performed with methyl green. Quantitative assessment was calculated as a percentage of TUNEL-positive nuclei.
Electron microscopy
For electron microscopic examination, tissues were fixed in a mixture of 2% paraformaldehyde, 2.5% glutardialdehyde, 0.13 mol/L cacodylate buffer, 0.025 mol/L CaCl2, and 2% saccharose; they were then osmicated (1%), dehydrated in graded ethanol, and embedded in epoxy resin. Ultrathin sections were counterstained with uranyl acetate and lead citrate and examined in a Zeiss EM902 electron microscope (Carl Zeiss, Oberkochen, Germany) operating at 80 kV. For negative staining, formvar-coated copper grids were placed on drops of prepared mitochondrial suspension for 2 minutes and excess liquid was drawn off with filter paper. The grids were then placed on drops of phosphotungstate (2%) for 1 minute and air-dried before electron microscopic examination.
Tissue preparation for biochemical analyses
Myocardial specimens were snap-frozen immediately after surgical removal and stored at -80°C until analyzed. Frozen muscle samples were mechanically homogenized in liquid nitrogen and resuspended in ice-cold buffer A (250 mmol/L sucrose, 20 mmol/L N-(2-hydroxyethyl)piperazine-N'-1-ethanesulfonic acid (HEPES), 10 mmol/L KCl, 1.5 mmol/L MgCl2, 1 mmol/L ethylenediaminetetraacetate (EDTA), 1 mmol/L ethylene glycol bis(2-aminoethyl)tetraacetic acid (EGTA), 1 mmol/L dithiothreitol, 17 µg/mL phenylmethylsulfonyl fluoride (PMSF), 8 µg/mL aprotinin, and 2 µg/mL leupeptin [pH 7.4]). The swollen cells were lysed by 15 strokes in an ice-cold, tightly fitting cylinder homogenizer. Unlysed cells and nuclei were removed by centrifugation at 750 g for 5 minutes at 4°C. The supernatant was spun at 10,000 g for 25 minutes at 4°C, and the resulting mitochondrial pellets were then resuspended in buffer A and frozen in multiple samples at -80°C. Supernatants were centrifuged at 100,000 g for 1 hour at 4°C. The supernatant of this final centrifugation, representing the S100 fraction, was divided into aliquots and stored at -80°C.
Determination of cytochrome c
Equal amounts of cytosolic protein, as determined by Bicinchoninic Protein Assay (BCA) kit (Sigma Chemical, St. Louis, MO) were separated by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (15% gel) followed by transfer to nitrocellulose filters. Blots were probed with monoclonal antibodies to cytochrome c (Pharmingen, San Diego, CA) used at a dilution of 1:5,000. The antigen–antibody complex was visualized on x-ray films using a secondary probe with horseradish peroxidase-labeled antibodies (Amersham, Buckinghamshire, UK) and a chemiluminescense kit (ECL; Amersham). Quantitative data were provided by densitometry of films. We included only those data that were obtained from a range showing the best linear correlation of measured signal intensity with cytochrome c amount in dilution rows of samples (R = 0.984, p < 0.001).
Determination of citrate synthase activity
A quantity of 10 µL of cytosolic protein was incubated with 810 µL H2O, 100 µL 5,5'-Dithio-bis(2-nitrobenzoic acid) solution (1 mmol/L in 1 mol/L Tris-HCl, pH 8.1), and 30 µL acetyl coenzyme A solution (12.5 mmol/L, pH 5). Coenzyme A production was monitored by measurement of absorption at 412 nm. After 2 minutes, 50 µL of 10 mmol/L sodium oxaloacetate (OAA) were added. For calculation of citrate synthase activity, the increase in absorption during 1 minute before addition of OAA (representing the acetyl-CoA hydrolase activity) was subtracted from the increase in absorption during the first minute of linearly increasing absorption after the addition of OAA. Regression analyses of dilution series with crystalline citrate synthase suspension (Sigma) confirmed linearity between the increase of absorption at 412 nm and enzyme activity for the range of measured values (R = 0.989, p < 0.001).
Data analysis
Data are presented as means ± standard errors. Values from heart biopsy specimens before and after cardioplegic arrest and reperfusion were compared using Student’s t test. Linear regression analyses and calculations of correlation coefficients were performed to determine the association of various factors such as the time of cardioplegic arrest and reperfusion with the levels of cytosolic cytochrome c, cytosolic citrate synthase activity, or the ratio of both.
|
Results |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
|---|
|
|
|
A marker enzyme for the mitochondrial matrix fraction is citrate synthase [11]. No citrate synthase spillage can be measured in preparations of intact mitochondria [11]. Detection of this enzyme in the cytosol presupposes rupture of both the outer and inner mitochondrial membranes. Our measurements displayed some citrate synthase activity in all cytosolic preparations ranging between 0.9 and 6.8 U/mg protein. Before cardioplegia and reperfusion the average citrate synthase activity in the cytosol was 1.9 ± 0.2 U/mg and afterward it was 3.7 ± 0.5 U/mg, demonstrating a 2.0 ± 0.3–fold increase (p < 0.005).
The proportion of mitochondria with cytochrome c release and intact inner mitochondrial membrane, as in early stages of the apoptotic program, can be defined by the ratio of cytochrome c and citrate synthase in the cytosol. This index showed an overall 1.7 ± 0.2–fold increase (p < 0.05) during surgery and correlated well with the duration of cardioplegic arrest and reperfusion (R = 0.634, p < 0.05; Fig 4).
To analyze whether this index also correlates with myocardial stunning, hemodynamic measurements were performed. Using pulmonary artery catheters left ventricular function was measured before cardioplegic arrest and after chest closure at the end of the surgical procedure. Pulmonary artery catheters were not placed in 3 patients who lacked any clinical indication for invasive monitoring. In 2 patients, postoperative hemodynamic data were biased by administration of catecholamines. The remaining 6 patients showed an increased cardiac index (
CI) of 1.65 ± 0.2 l min-1 · m-2 (p < 0.001) after surgery and no significant changes of pulmonary capillary wedge pressures (PCWP) and mean pulmonary artery pressures (PAPmean). As illustrated in Figure 5,
CI decreased with higher cytosolic cytochrome c/citrate synthase ratios (R = 0.736). Simultaneously, PCWP and PAPmean increased (R = 0.747 and R = 0.813, respectively).
|
|
of myocytes nuclei before, respectively 3.2 ± 1.3 after cardioplegic arrest and reperfusion (Fig 6),
ie, a nonsignificant 2.5 ± 1.2–fold increase (p = 0.14). Marked cells were found mainly in the subendocardial layers of the myocardium.
|
|
Comment |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
|---|
Using the TUNEL method we found fragmentation of DNA as in terminal stages of apoptosis in 3.2 ± 1.3 of myocytes at the end of surgery. Similar percentages of TUNEL-positive cells have been reported by others in samples obtained from failing hearts [15]. Even such a small number of cells affected by apoptosis may have a significant impact on cardiac contractility, because single-cell death impinges upon the force-generating ability of neighboring cells [16] that are still viable but stunned. Relatively few apoptotic cells may substantially impair side-to-side slippage of myocytes, resulting in a disproportionate and much more severe cardiac dysfunction [16]. Further, our results from TUNEL staining probably underestimate the overall incidence of apoptosis occurring with cardiac surgery, given that the entire apoptotic program takes 12 to 24 hours until completion in all cells [3] and the intraoperative time window for sample acquisition was confined to a maximum of 2.6 hours. To overcome this limitation, we investigated very early signs of apoptosis by electron microscopy and measurement of cytochrome c release. Because the TUNEL assay may also display positive staining in necrotic tissue, these experiments were also necessary to confirm the presence of apoptosis. The morphologic patterns observed by electron microscopy describe typical features of early phases of apoptotic cell death [2, 3]. The fact that insulated single myocytes were affected and that pericellular infiltration and edema were absent clearly distinguish the findings from those of necrosis [3]. Swelling and membrane rupture of mitochondria is likely to result in cell death, either by interruption of the respiratory chain and ATP production due to changes in electron transport and loss of transmembrane potential or by spilling of substances such as cytochrome c that promote apoptosis [1]. Release of cytochrome c from the intermembrane space into the cytosol is a central event during initiation of apoptosis in response to death stimuli [9, 10]. In this study, we found a highly significant 3.4 ± 0.4–fold increase (p < 0.0001) of cytochrome c in the cytosol of myocytes during open heart surgery. The 2.0 ± 0.3–fold increase (p < 0.005) in cytosolic activity of the matrix marker citrate synthase during open heart surgery suggests the coinvolvement of cell injury other than apoptosis in reperfusion injury after cardioplegic arrest of the heart. Such cell damage as well as technical influences on cytochrome c measurements (eg, tissue damage during preparation) were ruled out by the determination of ratios of cytochrome c and citrate synthase activity. This ratio increased significantly (1.7 ± 0.2–fold; p < 0.05) during cardioplegia and reperfusion of the human heart. Together with our findings from electron microscopy, these data provide clear evidence of early stages of programmed cell death.
Determination of cardiomyocyte apoptosis during open heart surgery is challenging for the several reasons. First, the surgical procedure limits the window of time for tissue sampling to about 2 hours. As mentioned earlier, the apoptotic program has just started at this point, and only its initial stages are detectable in the majority of cells undergoing programmed cell death. Furthermore, the percentage of affected cells is very low because of the cardioprotective strategies used during ischemia. Thus, highly sensitive markers are required for detection of apoptosis. As apoptosis often starts in mitochondria [1] and the volume density of mitochondria in cardiomyocytes (25%) is higher than in any other human cell type, mitochondrial markers such as cytochrome c appear to be promising. Finally, access to human heart tissue is limited, particularly that from ventricular sites. Appropriate amounts of heart tissue that are sufficient for exploration of apoptosis but do not confer risk for impairing cardiac function are most readily obtained from the atrial appendage. Because aortic cross-clamping and induction of cardioplegia through the aortic root affects the entire heart and for a constant duration, and because the ischemic threshold of cardiocytes is probably similar in the entire organ, we hypothesize that our findings in the right atria reflect changes in the entire heart. However, further studies using left ventricular tissue are necessary to support this hypothesis. The extrapolation from measurements made in the right atrial appendage to ventricular muscle still represents a limitation of the current work.
Cardiac function is generally improved after open heart surgery, partly because of surgical achievements and, initially, also because of better preload and afterload as well as pacing of the heart. Nevertheless, during the first few postoperative hours, right and left ventricular contractility decreases to 30% to 40% less than preoperative values, with a nadir of myocardial function between 4 and 6 hours after cardioplegia and reperfusion [17]. The decline in cardiac contractility correlates with the duration of cardioplegic arrest, which is directly related to patient mortality [18]. This holds also true for cardiac transplantation with a significant inverse correlation between the cardioplegic time of the transplanted heart and recipient survival [19]. In this study, the duration of cardioplegia and reperfusion increased with mitochondrial changes characteristic for apoptosis (ratio of cytochrome c and citrate synthase). The extent of these changes was further associated with a decline in left ventricular function, as revealed by measurements of patients’ hemodynamic. With increasing apoptotic alterations left ventricular performance deteriorated as shown for CI, PCWP, and PAPmean. These correlations suggest that myocardial apoptosis may contribute to postoperative myocardial depression. We hypothesize that programmed myocyte death may actually be the final consequence of oxygen free radical generation and other detrimental phenomena observed in the course of cardioplegia and reperfusion [20, 21].
Although dead myocytes cannot be replaced in adults, depressed cardiac function after open heart surgery is temporary and is compensated in the vast majority of patients. The clinical outcome for these patients is good, and long-term improvement is achieved by operative relief of pathologic cardiac conditions and compensatory mechanisms of the remaining myocytes, such as remodeling and hypertrophy. However, in patients with severely reduced heart function (left ventricular ejection fraction <25%) preoperatively, the risk of perioperative mortality increases up to 11% [22], illustrating the lowered tolerance of these patients for myocardial stunning after cardioplegia and reperfusion. A prerequisite for improvement of intraoperative protection of the heart and prevention of cardiac depression is a better understanding of myocardial pathophysiology during cardioplegic arrest and reperfusion. Our data suggest a potential role for programmed myocyte death in this setting. The ratio of cytosolic cytochrome c and citrate synthase provides a suitable marker for assessment of early apoptosis in heart tissue. This concept may provide a relevant assay for monitoring the value of surgical techniques such as coronary revascularization without cardiopulmonary bypass or without cardioplegic arrest. Development and inclusion of antiapoptotic agents in cardioplegic solutions ultimately may provide additional benefit for myocardial preservation.
|
Acknowledgments |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
|---|
|
References |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
|---|
Related Article
This article has been cited by other articles:
|
|
 |
|
  C. Chen-Scarabelli, G. Faggian, Z. Yuan, M. Tessari, A. Rungatscher, J. Di Rezze, G. M. Scarabelli, K. Abounit, R. McCauley, L. Saravolatz, et al. Warm-blood cardioplegic arrest induces selective mitochondrial translocation of protein kinase C{epsilon} followed by interaction with 6.1 inwardly rectifying potassium channel subunit in viable myocytes overexpressing urocortin J. Thorac. Cardiovasc. Surg., November 1, 2009; 138(5): 1213 - 1221. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-G. Ryou, D. C. Flaherty, B. Hoxha, J. Sun, H. Gurji, S. Rodriguez, G. Bell, A. H. Olivencia-Yurvati, and R. T. Mallet Pyruvate-fortified cardioplegia evokes myocardial erythropoietin signaling in swine undergoing cardiopulmonary bypass Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1914 - H1922. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. G. Leshnower, S. Kanemoto, M. Matsubara, H. Sakamoto, R. Hinmon, J. H. Gorman III, and R. C. Gorman Cyclosporine Preserves Mitochondrial Morphology After Myocardial Ischemia/Reperfusion Independent of Calcineurin Inhibition Ann. Thorac. Surg., October 1, 2008; 86(4): 1286 - 1292. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Shalaby, T. Rinne, O. Jarvinen, A. Saraste, J. Laurikka, H. Porkkala, P. Saukko, and M. Tarkka Initial results of a clinical study: adenosine enhanced cardioprotection and its effect on cardiomyocytes apoptosis during coronary artery bypass grafting Eur. J. Cardiothorac. Surg., April 1, 2008; 33(4): 639 - 644. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Oka, L. Wang, W. Mi, W. Zhu, O. Honjo, and C. A. Caldarone Cyclosporine A prevents apoptosis-related mitochondrial dysfunction after neonatal cardioplegic arrest J. Thorac. Cardiovasc. Surg., January 1, 2008; 135(1): 123 - 130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Malmberg, T. Vahasilta, A. Saraste, V. Kyto, J. Kiss, E. Kentala, M. Kallajoki, and T. Savunen Cardiomyocyte apoptosis and duration of aortic clamping in pig model of open heart surgery. Eur. J. Cardiothorac. Surg., September 1, 2006; 30(3): 480 - 484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Ramlawi, J. Feng, S. Mieno, C. Szabo, Z. Zsengeller, R. Clements, N. Sodha, M. Boodhwani, C. Bianchi, and F. W. Sellke Indices of Apoptosis Activation After Blood Cardioplegia and Cardiopulmonary Bypass Circulation, July 4, 2006; 114(1_suppl): I-257 - I-263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Wang, C. Kinnear, J. M. Hammel, W. Zhu, Z. Hua, W. Mi, and C. A. Caldarone Preservation of Mitochondrial Structure and Function After Cardioplegic Arrest in the Neonate Using a Selective Mitochondrial K(ATP) Channel Opener. Ann. Thorac. Surg., May 1, 2006; 81(5): 1817 - 1823. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Vahasilta, A. Saraste, V. Kyto, M. Malmberg, J. Kiss, E. Kentala, M. Kallajoki, and T. Savunen Cardiomyocyte Apoptosis After Antegrade and Retrograde Cardioplegia Ann. Thorac. Surg., December 1, 2005; 80(6): 2229 - 2234. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Feng, C. Bianchi, J. L. Sandmeyer, J. Li, and F. W. Sellke Molecular Indices of Apoptosis After Intermittent Blood and Crystalloid Cardioplegia Circulation, August 30, 2005; 112(9_suppl): I-184 - I-189. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Feng, C. Bianchi, J. L. Sandmeyer, and F. W. Sellke Bradykinin Preconditioning Improves the Profile of Cell Survival Proteins and Limits Apoptosis After Cardioplegic Arrest Circulation, August 30, 2005; 112(9_suppl): I-190 - I-195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Miwa, K. Yamazaki, S.-H. Hyon, and M. Komeda A novel method of 'preparative' myocardial protection using green tea polyphenol in oral uptake Interactive CardioVascular and Thoracic Surgery, December 1, 2004; 3(4): 612 - 615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Pitts and C. F. Toombs Coverslip hypoxia: a novel method for studying cardiac myocyte hypoxia and ischemia in vitro Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1801 - H1812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Caldarone, E. W. Barner, L. Wang, M. Karimi, C. E. Mascio, J. M. Hammel, J. L. Segar, C. Du, and T. D. Scholz Apoptosis-related mitochondrial dysfunction in the early postoperative neonatal lamb heart Ann. Thorac. Surg., September 1, 2004; 78(3): 948 - 955. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Scarabelli, E. Pasini, G. Ferrari, M. Ferrari, A. Stephanou, K. Lawrence, P. Townsend, C. Chen-Scarabelli, G. Gitti, L. Saravolatz, et al. Warm blood cardioplegic arrest induces mitochondrial-mediated cardiomyocyte apoptosis associated with increased urocortin expression in viable cells J. Thorac. Cardiovasc. Surg., September 1, 2004; 128(3): 364 - 371. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yamazaki, S. Miwa, K. Ueda, S. Tanaka, S. Toyokuni, O. Unimonh, K. Nishimura, and M. Komeda Prevention of myocardial reperfusion injury by poly(ADP-ribose) synthetase inhibitor, 3-aminobenzamide, in cardioplegic solution: in vitro study of isolated rat heart model Eur. J. Cardiothorac. Surg., August 1, 2004; 26(2): 270 - 275. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Yeh, Y.-M. Lin, Y.-C. Wu, Y.-C. Wang, and P. J. Lin Nitric oxide attenuates cardiomyocytic apoptosis via diminished mitochondrial complex I up-regulation from cardiac ischemia-reperfusion injury under cardiopulmonary bypass J. Thorac. Cardiovasc. Surg., August 1, 2004; 128(2): 180 - 188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Bloch and U. Mehlhorn Poly-adenosine diphosphate-ribose polymerase inhibition for myocardial protection: Pathophysiologic and physiologic considerations J. Thorac. Cardiovasc. Surg., August 1, 2004; 128(2): 323 - 324. [Full Text] [PDF]
|
|
|
|
|
|
U. M. Fischer, P. Tossios, A. Huebner, H. J. Geissler, W. Bloch, and U. Mehlhorn Myocardial apoptosis prevention by radical scavenging in patients undergoing cardiac surgery J. Thorac. Cardiovasc. Surg., July 1, 2004; 128(1): 103 - 108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Sayk, S. Kruger, J.F. M. Bechtel, A. C. Feller, H. H. Sievers, and C. Bartels Significant damage of the conduction system during cardioplegic arrest is due to necrosis not apoptosis Eur. J. Cardiothorac. Surg., May 1, 2004; 25(5): 801 - 806. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Feng, C. Bianchi, J. Li, and F. W. Sellke Improved profile of bad phosphorylation and caspase 3 activation after blood versus crystalloid cardioplegia Ann. Thorac. Surg., April 1, 2004; 77(4): 1384 - 1389. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Anselmi, A. Abbate, F. Girola, G. Nasso, G. G.L. Biondi-Zoccai, G. Possati, and M. Gaudino Myocardial ischemia, stunning, inflammation, and apoptosis during cardiac surgery: a review of evidence Eur. J. Cardiothorac. Surg., March 1, 2004; 25(3): 304 - 311. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Karimi, L. X. Wang, J. M. Hammel, C. E. Mascio, M. Abdulhamid, E. W. Barner, T. D. Scholz, J. L. Segar, W. G. Li, S. D. Niles, et al. Neonatal vulnerability to ischemia and reperfusion: Cardioplegic arrest causes greater myocardial apoptosis in neonatal lambs than in mature lambs J. Thorac. Cardiovasc. Surg., February 1, 2004; 127(2): 490 - 497. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Sayk and C. Bartels Oncosis rather than apoptosis? Ann. Thorac. Surg., January 1, 2004; 77(1): 382 - 382. [Full Text] [PDF]
|
|
|
|
 |
|
 C.-H. Yeh, J.-H. S. Pang, Y.-C. Wu, Y.-C. Wang, J.-J. Chu, and P. J. Lin Differential-Display Polymerase Chain Reaction Identifies Nicotinamide Adenine Dinucleotide-Ubiquinone Oxidoreductase as an Ischemia/Reperfusion-Regulated Gene in Cardiomyocytes Chest, January 1, 2004; 125(1): 228 - 235. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Schmitt and H. Aebert Reply Ann. Thorac. Surg., January 1, 2004; 77(1): 382 - 382. [Full Text] [PDF]
|
|
|
|
|
|
Z.-K. Wu, J. Laurikka, A. Saraste, V. Kyto, E. J. Pehkonen, T. Savunen, and M. R. Tarkka Cardiomyocyte apoptosis and ischemic preconditioning in open heart operations Ann. Thorac. Surg., August 1, 2003; 76(2): 528 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z.-Q. Z.-Q. Zhao, C. D. Morris, J. M. Budde, N.-P. N.-P. Wang, S. Muraki, H.-Y. H.-Y. Sun, and R. A. Guyton Inhibition of myocardial apoptosis reduces infarct size and improves regional contractile dysfunction during reperfusion Cardiovasc Res, July 1, 2003; 59(1): 132 - 142. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Hammel, C. A. Caldarone, T. L. Van Natta, L. X. Wang, K. F. Welke, W. Li, S. Niles, E. Barner, T. D. Scholz, D. M. Behrendt, et al. Myocardial apoptosis after cardioplegic arrest in the neonatal lamb J. Thorac. Cardiovasc. Surg., June 1, 2003; 125(6): 1268 - 1275. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Valen The basic biology of apoptosis and its implications for cardiac function and viability Ann. Thorac. Surg., February 1, 2003; 75(2): S656 - 660. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
, 
, 