(Circulation. 1997;95:320-323.)
© 1997 American Heart Association, Inc.
Articles |
Apoptosis in Human Acute Myocardial Infarction
the Departments of Anatomy (A.S., K.H., M.P.), Clinical Chemistry (K.P.), Pathology (M.K.), and Medicine (A.S., L.-M.V.-P.), University of Turku, Kiinamyllynkatu 4-8, Finland.
Correspondence to Liisa-Maria Voipio-Pulkki, MD, Department of Medicine, University of Turku, FIN-20520 Turku, Finland. E-mail liisa-maria.voipio-pulkki{at}utu.fi
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Abstract |
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Background After reopening of the infarct-related coronary artery, cardiomyocytes continue to die during reperfusion. The mechanisms of cell death have been subject to debate. We studied whether an apoptotic type of cell death occurs in human acute myocardial infarction (AMI).
Methods and Results We studied myocardial samples of eight patients who died of AMI and had patent infarct-related arteries at autopsy. Six of the patients had received initially successful thrombolysis. Extensive formation of DNA strand breaks, the typical biochemical feature of apoptosis, was detected with the use of the in situ DNA end-labeling method. Apoptotic cardiomyocytes were observed particularly in the border zones of histologically infarcted myocardium, whereas very few apoptotic cells were present in the remote noninfarcted myocardium. Internucleosomal fragmentation was confirmed by agarose gel electrophoresis of DNA isolated from the representative myocardial areas.
Conclusions This study provides evidence that in addition to overt necrosis, a subset of myocytes undergo apoptosis during ischemia-reperfusion injury. Apoptosis may provide a new target for cardioprotection during evolving AMI in humans.
Key Words: apoptosis • myocardial infarction • reperfusion • ischemia • thrombolysis
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Introduction |
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Opening of the infarct-related coronary artery is a valued therapeutic goal in acute myocardial infarction (AMI). However, cardiomyocytes continue to die during reperfusion. The mechanisms of cell death during this phase of AMI have been subject to debate.1 Apoptosis is a morphologically distinct, genetically controlled type of cell death.2 3 Extensive fragmentation of genomic DNA into nucleosome-sized fragments by endogenous endonucleases is the biochemical hallmark of apoptosis.4
Various physiological regulators and exposures to noxious stimuli can activate apoptosis.3 Experimental evidence suggests that cardiomyocytes are able to undergo apoptosis during hypoxia,5 myocardial infarction,6 heart failure,7 and ischemia-reperfusion.8 To explore the clinical relevance of these findings, we studied whether myocardial apoptosis occurred in human AMI after reopening of the coronary artery, the clinical counterpart of ischemia-reperfusion injury. Apoptosis was demonstrated by detecting DNA strand breaks with the in situ end-labeling (ISEL) technique, and internucleosomal fragmentation was confirmed by agarose gel electrophoresis of isolated DNA. Histological features of ISEL-positive areas were characterized by van Gieson staining of corresponding myocardial sections.
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Methods |
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Tissue Sampling
Tissue samples were obtained from autopsies of 14 patients. In 8 patients (Table
), AMI was diagnosed clinically by symptoms, ECG changes, and elevated serum levels of cardiac enzymes. Intravenous thrombolytic therapy was administered in 6 patients and resulted in initial alleviation of chest pain and ST-segment elevations as well as a rapid leakage of cardiac enzymes. Two patients (patients 7 and 8 in the Table) presented with chest pain, deep ST-segment depressions, and elevated cardiac enzymes but did not receive thrombolysis. In all AMI patients, autopsy revealed multivessel coronary artery disease and severe but not total obstruction of the infarct-related artery, supporting the clinical judgment of initially successful thrombolysis (patients 1 through 6) or suggesting spontaneous subendocardial ischemia-reperfusion (patients 7 and 8, who also showed hemorrhagic infarction in histological sections). Six patients who died of noncardiac causes (Table) served as control patients. The tissue collection procedures were approved by the National Board of Medicolegal Affairs in Finland.
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Transmural myocardial tissue samples from infarcted, border-zone, and remote areas of infarcted hearts and from the left ventricles of noninfarcted hearts were fixed in 10% neutral buffered formalin for 24 hours, embedded in paraffin, and cut in 4-µm sections for ISEL and van Gieson staining. Comparable samples were frozen in liquid nitrogen for isolation of DNA.
Detection of Apoptosis
DNA strand breaks in tissue sections were 3'-end labeled with digoxigenin-conjugated dideoxy-UTP by terminal deoxynucleotidyltransferase and detected immunohistochemically with digoxigenin antibody conjugated to alkaline phosphatase, as described previously.8 9 Sections were pretreated with sodium citrate and proteinase K to improve the accessibility of DNA. The intensity of immunohistochemical staining was monitored continuously by light microscopy to confirm optimal sensitivity of the assay. The maximal incubation time was determined by the first appearance of positivity in samples from control patient hearts. Sections pretreated with DNAase I (1 U/mL) for 30 minutes at 37°C were intensely positive at this time. Reagents were purchased from Boehringer Mannheim, except dideoxy-ATP from Pharmacia and DNAase I from Sigma Chemical Co.
To confirm the apoptotic nature of DNA fragmentation, we performed autoradiographic analysis of electrophoretically fractionated and [32P]dideoxy-ATP (Amersham) end-labeled DNA according to previously described methodology.10 DNA was isolated from ISEL-positive and -negative areas in two patients and from areas of infarction, border-zone, and remote myocardium in another two patients.
Histological Analysis
The number of ISEL-positive myocytes and their percentage of total cardiocytes were counted with the use of a microscope with an eyepiece grid (magnification x200). An average of 1800 fields were analyzed per patient. Histological features of ISEL-stained sections were determined by comparison with adjacent, serial sections stained with van Gieson. Samples from all AMI patients contained histological features of recent infarction: neutrophil infiltration, eosinophilia, cellular edema, nuclear changes, contraction bands, and coagulation necrosis.
Statistical Analysis
The percentages of apoptotic cardiomyocytes in the infarcted, border-zone, and remote areas of the AMI hearts, expressed as mean±SD, were compared by use of Student's t test for paired data. Differences were considered significant at a value of P<.05.
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Results |
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In samples from each AMI patient, intense ISEL-staining of nuclei in some cardiomyocytes was observed, indicating extensive formation of DNA strand breaks. Electrophoretically separated DNA, isolated from the ISEL-positive areas, showed the characteristic ladder pattern in autoradiography (Fig 1a
), thus confirming the internucleosomal fragmentation typical of apoptosis. On the other hand, comparison of DNA fragmentation in the border zones versus central areas of infarction revealed more unspecific degradation in the central areas, visible as a smear in the autoradiogram (Fig 1b). No detectable ladders were seen in the remote, noninfarcted areas. In all cases, clusters of apoptotic myocytes were detected particularly in the border zones of histologically recent infarction (Fig 2, a through d). Many apoptotic cells were also present adjacent to scars of previous infarcts (Fig 2, e and f) and in the endocardial regions adjacent to infarction. Some ISEL-positive inflammatory cells were detected, but their distribution showed no relation to the infarction and border-zone areas.
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Fig 3 shows that the percentage of apoptotic cells was significantly higher in the border zones compared with the central infarction areas (0.806±0.391% versus 0.039±0.027%; P=.0007). The amount of apoptosis in the remote noninfarcted segments (0.005±0.003%) did not differ from the control patient hearts (0.007±0.004%).
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Discussion |
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Experimental studies have shown that cardiomyocyte apoptosis is induced during hypoxia5 and ischemia-reperfusion.8 A specific association with reperfusion injury has even been suggested.8 The occurrence of cardiomyocyte apoptosis in the border zone of human myocardial infarction has also been described.11 The present study provides evidence that in addition to overt necrosis, a subset of myocytes undergoes apoptosis after AMI in patients with patent infarct-related arteries. These patients represent the clinical counterpart of experimental ischemia-reperfusion injury. Factors known to be associated with both ischemia-reperfusion injury and apoptosis include oxygen-derived free radicals,1 3 alterations of intracellular calcium homeostasis,1 3 increased mechanical stretch,6 and inflammatory reaction.3 12
The biochemical features of apoptosis have been described previously in histologically infarcted human myocardium.13 We found apoptotic cells to be significantly more numerous in the border zones of infarcted tissue, where percentages as high as 5.1% per microscopic field were occasionally observed. Because the time needed for a single cell to undergo apoptosis is probably very short, this process may allow considerable loss of cardiomyocytes in the vulnerable myocardial areas during the postinfarction recovery period.2 6 9 This possibility is further supported by the fact that we found the apoptotic type of cell death to be present days after initial reperfusion therapy as well as in the early phases of AMI.
Consistent with previous studies on myocardial ischemia-reperfusion,8 we did not detect clear apoptotic bodies of cardiomyocytic origin in routine histological sections. We suggest two possible explanations. First, apoptotic cells may be rapidly phagocytosed by the neighboring inflammatory cells.3 8 12 Second, the late stages of cardiomyocyte apoptosis and necrosis may share common morphological features, as was recently suggested by Kajstura and coworkers.6 However, in our sections, ISEL-positive cells showed no features of coagulative necrosis, which was otherwise detected in the central areas of infarction.
In conclusion, we have shown that cardiomyocyte apoptosis occurs in human AMI. Because apoptosis represents a potentially preventable form of cell death owing to its active nature, this finding may have important clinical implications as new cardioprotective treatment strategies are developed.
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Acknowledgments |
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This work has been supported financially by the Academy of Finland and the Finnish Heart Association.
Received September 30, 1996; revision received November 18, 1996; accepted November 20, 1996.
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References |
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1. Kloner RA. Does reperfusion injury exist in humans? J Am Coll Cardiol. 1993;21:537-545.[Abstract]
2. Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26:239-257.[Medline] [Order article via Infotrieve]
3.
Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. 1995;267:1456-1462.
4. Arends MJ, Morris RG, Wyllie AH. Apoptosis: the role of the endonuclease. Am J Pathol. 1990;136:593-608.[Abstract]
5.
Tanaka M, Hiroshi I, Adachi S, Akimoto H, Nishikawa T, Kasajima T, Marumo F, Hiroe M. Hypoxia induces apoptosis with enhanced expression of Fas antigen messenger RNA in cultured neonatal rat cardiomyocytes. Circ Res. 1994;75:426-433.
6. Kajstura J, Cheng W, Reiss K, Clark WA, Sonnenblick EH, Krajewski S, Reed JC, Olivetti G, Anversa P. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab Invest. 1996;74:86-107.[Medline] [Order article via Infotrieve]
7. Sharov VG, Sabbah HN, Shimoyama H, Goussev AV, Lesch M, Goldstein S. Evidence of cardiocyte apoptosis in myocardium of dogs with chronic heart failure. Am J Pathol. 1996;148:141-149.[Abstract]
8. Gottlieb RA, Burleson KA, Kloner RA, Babior BM, Engler RL. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest. 1994;94:1621-1628.
9.
Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992;119:493-501.
10. Tilly JL, Hsueh AJW. Microscale autoradiographic method for the qualitative and quantitative analysis of apoptotic DNA fragmentation. J Cell Physiol. 1993;154:519-526.[Medline] [Order article via Infotrieve]
11. Quaini F, Cigola E, Sala R, Andreoli AM, Giordano G, Lagrasta C, Maestri R, Olivetti G. Apoptosis in the infarcted human heart. BAM. 1996;6:241-249.
12. Entman ML, Michael L, Rossen RD, Dreyer WJ, Anderson DC, Taylor AA, Smith CW. Inflammation in the course of early myocardial ischemia. FASEB J. 1991;5:2529-2537.[Abstract]
13. Itoh G, Tamura J, Suzuki M, Suzuki Y, Ikeda H, Koike M, Nomura M, Jie T, Ito K. DNA fragmentation of human infarcted myocardial cells demonstrated by the nick end labeling method and DNA agarose gel electrophoresis. Am J Pathol. 1995;146:1325-1331.[Abstract]
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|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
H.-R. Liu, L. Tao, E. Gao, B. L Lopez, T. A Christopher, R. N Willette, E. H Ohlstein, T.-L. Yue, and X.-L. Ma Anti-apoptotic effects of rosiglitazone in hypercholesterolemic rabbits subjected to myocardial ischemia and reperfusion Cardiovasc Res, April 1, 2004; 62(1): 135 - 144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Eefting, B. Rensing, J. Wigman, W. J. Pannekoek, W. M. Liu, M. J. Cramer, D. J Lips, and P. A Doevendans Role of apoptosis in reperfusion injury Cardiovasc Res, February 15, 2004; 61(3): 414 - 426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. van der Meer, A. A. Voors, E. Lipsic, W. H. van Gilst, and D. J. van Veldhuisen Erythropoietin in cardiovascular diseases Eur. Heart J., February 2, 2004; 25(4): 285 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. M. Yarbrough, R. Mukherjee, G. P. Escobar, J. A. Sample, J. E. McLean, K. B. Dowdy, J. W. Hendrick, W. C. Gibson, A. E. Hardin, J. T. Mingoia, et al. Pharmacologic inhibition of intracellular caspases after myocardial infarction attenuates left ventricular remodeling: a potentially novel pathway J. Thorac. Cardiovasc. Surg., December 1, 2003; 126(6): 1892 - 1899. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q Z Feng, T D Li, L X Wei, X Qiao, J Yi, L Wang, and T S Yang Tempero-spatial dissociation between the expression of Fas and apoptosis after coronary occlusion Mol. Pathol., December 1, 2003; 56(6): 362 - 367. [Abstract] [Full Text] [PDF]
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|
|
C. B. Granger, K. W. Mahaffey, W. D. Weaver, P. Theroux, J. S. Hochman, T. G. Filloon, S. Rollins, T. G. Todaro, J. C. Nicolau, W. Ruzyllo, et al. Pexelizumab, an Anti-C5 Complement Antibody, as Adjunctive Therapy to Primary Percutaneous Coronary Intervention in Acute Myocardial Infarction: The COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) Trial Circulation, September 9, 2003; 108(10): 1184 - 1190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Gonzalez, M. A Fortuno, R. Querejeta, S. Ravassa, B. Lopez, N. Lopez, and J. Diez Cardiomyocyte apoptosis in hypertensive cardiomyopathy Cardiovasc Res, September 1, 2003; 59(3): 549 - 562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Inagaki, H. S. Hahn, G. W. Dorn II, and D. Mochly-Rosen Additive Protection of the Ischemic Heart Ex Vivo by Combined Treatment With {delta}-Protein Kinase C Inhibitor and {epsilon}-Protein Kinase C Activator Circulation, August 19, 2003; 108(7): 869 - 875. [Abstract] [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]
|
|
|
|
|
|
U. M. Fischer, O. Klass, U. Stock, J. Easo, H. J. Geissler, J. H. Fischer, W. Bloch, and U. Mehlhorn Cardioplegic arrest induces apoptosis signal-pathway in myocardial endothelial cells and cardiac myocytes Eur. J. Cardiothorac. Surg., June 1, 2003; 23(6): 984 - 990. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-H. Yeh, Y.-C. Wang, Y.-C. Wu, J.-J. Chu, and P. J. Lin Continuous Tepid Blood Cardioplegia Can Preserve Coronary Endothelium and Ameliorate the Occurrence of Cardiomyocyte Apoptosis Chest, May 1, 2003; 123(5): 1647 - 1654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Fortuno, A. Gonzalez, S. Ravassa, B. Lopez, and J. Diez Clinical implications of apoptosis in hypertensive heart disease Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1495 - H1506. [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ogata, M. Takahashi, S. Ueno, K. Takeuchi, T. Okada, H. Mano, S. Ookawara, K. Ozawa, B. C. Berk, U. Ikeda, et al. Antiapoptotic Effect of Endothelin-1 in Rat Cardiomyocytes In Vitro Hypertension, May 1, 2003; 41(5): 1156 - 1163. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Jiang, Y. Huang, S. Hunyor, and C.G. dos Remedios Cardiomyocyte apoptosis is associated with increased wall stress in chronic failing left ventricle Eur. Heart J., April 2, 2003; 24(8): 742 - 751. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Mani and R. N. Kitsis Myocyte apoptosis: programming ventricular remodeling J. Am. Coll. Cardiol., March 5, 2003; 41(5): 761 - 764. [Full Text] [PDF]
|
|
|
|
 |
|
 P. W.L. Thimister, L. Hofstra, I. H. Liem, H. H. Boersma, G. Kemerink, C. P.M. Reutelingsperger, and G. A.K. Heidendal In Vivo Detection of Cell Death in the Area at Risk in Acute Myocardial Infarction J. Nucl. Med., March 1, 2003; 44(3): 391 - 396. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Backlund, E. Palojoki, A. Saraste, T. Gronholm, A. Eriksson, P. Lakkisto, O. Vuolteenaho, M. S Nieminen, L.-M. Voipio-Pulkki, M. Laine, et al. Effect of vasopeptidase inhibitor omapatrilat on cardiomyocyte apoptosis and ventricular remodeling in rat myocardial infarction Cardiovasc Res, March 1, 2003; 57(3): 727 - 737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Lee, M. Sata, D. J. Lefer, S. M. Factor, K. Walsh, and R. N. Kitsis Fas pathway is a critical mediator of cardiac myocyte death and MI during ischemia-reperfusion in vivo Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H456 - H463. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. C. Gorman, J. H. Gorman III, and L. H. Edmunds Jr. Ischemic Mitral Regurgitation Card. Surg. Adult, January 1, 2003; 2(2003): 751 - 769. [Full Text]
|
|
|
|
|
|
P. Liu, B. Xu, T. A Cavalieri, and C. E Hock Age-related difference in myocardial function and inflammation in a rat model of myocardial ischemia-reperfusion Cardiovasc Res, December 1, 2002; 56(3): 443 - 453. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P A J Krijnen, R Nijmeijer, C J L M Meijer, C A Visser, C E Hack, and H W M Niessen Apoptosis in myocardial ischaemia and infarction J. Clin. Pathol., November 1, 2002; 55(11): 801 - 811. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Ratcliffe Non-ischemic infarct extension: A new type of infarct enlargement and a potential therapeutic target J. Am. Coll. Cardiol., September 18, 2002; 40(6): 1168 - 1171. [Full Text] [PDF]
|
|
|
|
|
|
A. Todor, V. G. Sharov, E. J. Tanhehco, N. Silverman, A. Bernabei, and H. N. Sabbah Hypoxia-induced cleavage of caspase-3 and DFF45/ICAD in human failed cardiomyocytes Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H990 - H995. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Akao, Y. Teshima, and E. Marban Antiapoptotic effect of nicorandil mediated by mitochondrial atp-sensitive potassium channels in cultured cardiac myocytes J. Am. Coll. Cardiol., August 21, 2002; 40(4): 803 - 810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-Q. Zhao and J. Vinten-Johansen Myocardial apoptosis and ischemic preconditioning Cardiovasc Res, August 15, 2002; 55(3): 438 - 455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Garcia-Dorado, M. Ruiz-Meana, F. Padilla, A. Rodriguez-Sinovas, and M. Mirabet Gap junction-mediated intercellular communication in ischemic preconditioning Cardiovasc Res, August 15, 2002; 55(3): 456 - 465. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.D. Dispersyn, L. Mesotten, B. Meuris, A. Maes, L. Mortelmans, W. Flameng, F. Ramaekers, and M. Borgers Dissociation of cardiomyocyte apoptosis and dedifferentiation in infarct border zones Eur. Heart J., June 1, 2002; 23(11): 849 - 857. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R Bennett APOPTOSIS IN THE CARDIOVASCULAR SYSTEM Heart, May 1, 2002; 87(5): 480 - 487. [Full Text] [PDF]
|
|
|
|
|
|
J. P. Schmitt, J. Schroder, H. Schunkert, D. E. Birnbaum, and H. Aebert Role of apoptosis in myocardial stunning after open heart surgery Ann. Thorac. Surg., April 1, 2002; 73(4): 1229 - 1235. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Liu, H. Y. Zhang, X. Zhu, Z. Shao, and Z. Yao Preconditioning blocks cardiocyte apoptosis: role of KATP channels and PKC-epsilon Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1380 - H1386. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shimizu, K. Fukuo, S. Nagata, T. Suhara, M. Okuro, K. Fujii, Y. Higashino, M. Mogi, Y. Hatanaka, and T. Ogihara Increased plasma levels of the soluble form of fas ligand in patients with acute myocardial infarction and unstable angina pectoris J. Am. Coll. Cardiol., February 20, 2002; 39(4): 585 - 590. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. GILL, R. MESTRIL, and A. SAMALI Losing heart: the role of apoptosis in heart disease--a novel therapeutic target? FASEB J, February 1, 2002; 16(2): 135 - 146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shizukuda and P. M. Buttrick Protein kinase C-zeta modulates thromboxane A2-mediated apoptosis in adult ventricular myocytes via Akt Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H320 - H327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Leicht, W. Briest, A. Holzl, and H.-G. Zimmer Serum depletion induces cell loss of rat cardiac fibroblasts and increased expression of extracellular matrix proteins in surviving cells Cardiovasc Res, December 1, 2001; 52(3): 429 - 437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Mallat, P. Fornes, R. Costagliola, B. Esposito, J. Belmin, D. Lecomte, and A. Tedgui Age and Gender Effects on Cardiomyocyte Apoptosis in the Normal Human Heart J. Gerontol. A Biol. Sci. Med. Sci., November 1, 2001; 56(11): M719 - 723. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Shiraishi, T. Tatsumi, N. Keira, K. Akashi, A. Mano, S. Yamanaka, S. Matoba, J. Asayama, T. Yaoi, S. Fushiki, et al. Important role of energy-dependent mitochondrial pathways in cultured rat cardiac myocyte apoptosis Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1637 - H1647. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D Tousoulis, G J Davies, C Tentolouris, G Goumas, C Stefanadis, and P Toutouzas Vasomotor effects of L- and D-arginine in stenotic atheromatous coronary plaque Heart, September 1, 2001; 86(3): 296 - 301. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Liu, B. C. McPherson, and Z. Yao Preconditioning attenuates apoptosis and necrosis: role of protein kinase C{epsilon} and -{delta} isoforms Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H404 - H410. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Palojoki, A. Saraste, A. Eriksson, K. Pulkki, M. Kallajoki, L.-M. Voipio-Pulkki, and I. Tikkanen Cardiomyocyte apoptosis and ventricular remodeling after myocardial infarction in rats Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2726 - H2731. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Palmen, M.J.A.P. Daemen, R. Bronsaer, W.R.M. Dassen, H.R. Zandbergen, M. Kockx, J.F.M. Smits, R. van der Zee, and P.A. Doevendans Cardiac remodeling after myocardial infarction is impaired in IGF-1 deficient mice Cardiovasc Res, June 1, 2001; 50(3): 516 - 524. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. E Basile-Borgia and V. C Ware Life and death of a cardiac myocyte: principles of cellular biology Perfusion, May 1, 2001; 16(3): 229 - 241. [Abstract] [PDF]
|
|
|
|
 |
|
 G. D. Dispersyn and M. Borgers Apoptosis in the Heart: About Programmed Cell Death and Survival Physiology, February 1, 2001; 16(1): 41 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D Tousoulis, C Tentolouris, T Crake, G Goumas, C Stefanadis, P Toutouzas, and G Davies Complex stenosis morphology and vasomotor responses to inhibition of nitric oxide synthesis Heart, November 1, 2000; 84(5): 529 - 534. [Abstract] [Full Text]
|
|
|
|
|
|
K. Yasui, K. Kada, M. Hojo, J.-K. Lee, K. Kamiya, J. Toyama, T. Opthof, and I. Kodama Cell-to-cell interaction prevents cell death in cultured neonatal rat ventricular myocytes Cardiovasc Res, October 1, 2000; 48(1): 68 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Imanishi, C. E. Murry, H. Reinecke, T. Hano, I. Nishio, W.C. Liles, L. Hofsta, K. Kim, K. D. O'Brien, S. M. Schwartz, et al. Cellular FLIP is expressed in cardiomyocytes and down-regulated in TUNEL-positive grafted cardiac tissues Cardiovasc Res, October 1, 2000; 48(1): 101 - 110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Myocardial Myocardial infarction redefined--A consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction Eur. Heart J., September 2, 2000; 21(18): 1502 - 1513. [Abstract] [PDF]
|
|
|
|
|
|
I. Jeremias, C. Kupatt, A. Martin-Villalba, H. Habazettl, J. Schenkel, P. Boekstegers, and K. M. Debatin Involvement of CD95/Apo1/Fas in Cell Death After Myocardial Ischemia Circulation, August 22, 2000; 102(8): 915 - 920. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Kang and S. Izumo Apoptosis and Heart Failure : A Critical Review of the Literature Circ. Res., June 9, 2000; 86(11): 1107 - 1113. [Full Text] [PDF]
|
|
|
|
|
|
N. Latif, M. A. Khan, E. Birks, A. O'Farrell, J. Westbrook, M. J. Dunn, and M. H. Yacoub Upregulation of the Bcl-2 family of proteins in end stage heart failure J. Am. Coll. Cardiol., June 1, 2000; 35(7): 1769 - 1777. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. N. James Homage to James B. Herrick: A Contemporary Look at Myocardial Infarction and at Sickle-Cell Heart Disease : The 32nd Annual Herrick Lecture of the Council on Clinical Cardiology of the American Heart Association Circulation, April 18, 2000; 101(15): 1874 - 1887. [Full Text] [PDF]
|
|
|
|
 |
|
 O. J. Arola, A. Saraste, K. Pulkki, M. Kallajoki, M. Parvinen, and L.-M. Voipio-Pulkki Acute Doxorubicin Cardiotoxicity Involves Cardiomyocyte Apoptosis Cancer Res., April 1, 2000; 60(7): 1789 - 1792. [Abstract] [Full Text]
|
|
|
|
|
|
H. Spitznagel, O. Chung, Q.-G. Xia, B. Rossius, S. Illner, G. Jahnichen, S. Sandmann, A. Reinecke, M. J.A.P. Daemen, and T. Unger Cardioprotective effects of the Na+/H+-exchange inhibitor cariporide in infarct-induced heart failure Cardiovasc Res, April 1, 2000; 46(1): 102 - 110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-i. Abe, C. P. Baines, and B. C. Berk Role of Mitogen-Activated Protein Kinases in Ischemia and Reperfusion Injury : The Good and the Bad Circ. Res., March 31, 2000; 86(6): 607 - 609. [Full Text] [PDF]
|
|
|
|
|
|
A. Haunstetter and S. Izumo Toward Antiapoptosis as a New Treatment Modality Circ. Res., March 3, 2000; 86(4): 371 - 376. [Full Text] [PDF]
|
|
|
|
|
|
L. J. De Windt, H. W. Lim, T. Taigen, D. Wencker, G. Condorelli, G. W. Dorn II, R. N. Kitsis, and J. D. Molkentin Calcineurin-Mediated Hypertrophy Protects Cardiomyocytes From Apoptosis In Vitro and In Vivo : An Apoptosis-Independent Model of Dilated Heart Failure Circ. Res., February 18, 2000; 86(3): 255 - 263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Saraste and K. Pulkki Morphologic and biochemical hallmarks of apoptosis Cardiovasc Res, February 1, 2000; 45(3): 528 - 537. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Yaoita, K. Ogawa, K. Maehara, and Y. Maruyama Apoptosis in relevant clinical situations: contribution of apoptosis in myocardial infarction Cardiovasc Res, February 1, 2000; 45(3): 630 - 641. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-Q. Zhao, M. Nakamura, N.-P. Wang, J. N. Wilcox, S. Shearer, R. S. Ronson, R. A. Guyton, and J. Vinten-Johansen Reperfusion induces myocardial apoptotic cell death Cardiovasc Res, February 1, 2000; 45(3): 651 - 660. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D. Dispersyn, M. Borgers, and W. Flameng Apoptosis in chronic hibernating myocardium: sleeping to death? Cardiovasc Res, February 1, 2000; 45(3): 696 - 703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. N. Sabbah Apoptotic cell death in heart failure Cardiovasc Res, February 1, 2000; 45(3): 704 - 712. [Full Text] [PDF]
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