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1 Minerva Institute for Medical Research, Departments of 2 Medicine and 5 Clinical Chemistry, Helsinki University Central Hospital, Helsinki FIN-00029; and Departments of 3 Anatomy, 4 Medicine, and 6 Pathology, University of Turku, Turku FIN-20520, Finland
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We investigated the role of cardiomyocyte apoptosis in the remodeling of the left ventricle from 24 h to 12 wk after myocardial infarction in the rat. Infarct size planimetry, quantification of cardiomyocyte apoptosis, terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) methodology, and echocardiography (left ventricular diastolic diameter and ejection fraction) were performed. Sham-operated animals showed low rates of cardiomyocyte apoptosis (0.03%) and no change in diastolic diameter or ejection fraction during the study. Twenty-four hours after infarction, TUNEL positivity was high in the infarct areas (1.4%) and border zones (4.9%). It declined to 0.34% (P < 0.01 vs. sham) at 4 wk and 0.10% at 12 wk in the border zones. In the remote myocardium, cardiomyocyte apoptosis increased to 0.07% (P = 0.03 vs. sham) on day 1 and remained on the same level up to 4 wk. The increase in diastolic diameter 1-4 wk after infarction correlated (r = 0.60, P < 0.01) with cardiomyocyte apoptosis in the noninfarcted myocardium, which quantitatively contributed most (>50%) to the apoptotic cell loss by 4 wk.
ischemia
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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LEFT VENTRICULAR (LV) remodeling after myocardial infarction (MI) involves expansion of the infarcted area, ventricular dilatation, and thinning of the ventricular wall (20, 22, 28). Cellular mechanisms of this process include myocyte hypertrophy, elongation, and topographic rearrangements, such as side-to-side slippage (20).
Apoptosis is a distinct type of cell death characterized by a series of typical morphological events, such as shrinkage of the cell, fragmentation into membrane-bound apoptotic bodies, and rapid phagocytosis into neighboring cells without induction of inflammatory response (15). The biochemical hallmark of apoptosis is internucleosomal DNA fragmentation (30). Cardiomyocyte apoptosis has recently been shown to occur in ischemic and reperfused myocardium both in animal models (1, 5, 8, 13) and in humans (12, 24). Moreover, apoptosis has been found in viable myocardial areas after MI (3, 21, 24) and in experimental (26) and human ischemic heart failure (17, 19, 25).
To clarify the role of apoptosis in chronic post-MI remodeling, we studied the time course and anatomic distribution of cardiomyocyte apoptosis in rat MI. We assessed the occurrence of cardiomyocyte apoptosis from 24 h to 12 wk after infarction in the infarcted, border zone and remote noninfarcted myocardial regions and compared the proportions of apoptotic myocytes with echocardiographic measures of the remodeling process.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental MI and tissue sampling. MI was produced by ligation of the left anterior descending coronary artery. Briefly, adult male Wistar rats weighing 350-500 g were anesthetized subcutaneously by using 0.5 mg/kg of medetomidine (Domitor, Orion; Turku, Finland) and with 70-80 mg/kg ip ketamine (Ketalar, Parke-Davis; Barcelona, Spain). The rats were connected to a respirator through a tracheotomy, and the heart was rapidly exteriorized through a left thoracotomy and pericardial incision. The coronary artery was ligated about 3 mm from its origin, the heart was returned to its normal position, and the thorax was closed. Throughout the operation, the body was maintained at a stable temperature with the use of a thermal plate. The anesthesia was partially antagonized with atipamezole hydrochloride (0.75 mg/kg sc, Antisedan; Orion), and the rats were disconnected from the respirator. The rats were hydrated postoperatively with 10 ml sc of physiological saline and given 0.02 mg/kg sc of buprenorphine hydrocholoride (Temgesic; Reckitt and Colman; Hull, UK) twice for analgesia. The control rats underwent the same procedure except for the ligation of the coronary artery (sham operation).
After 24 h, 1 wk, 4 wk, and 12 wk after coronary ligation, the rats were euthanized with CO2 (n = 6-14 rats in each group). The heart was excised and cut into 2-mm transverse slices below the point where the coronary artery was ligated. The myocardial samples were fixed in 4% neutral-buffered formalin for 24 h, embedded in paraffin, and cut in 4-µm- thick sections for histology, planimetry, and assessment of apoptosis.Echocardiography. All of the experimental animals underwent echocardiography under anesthesia just before the operation (baseline) and 24 h, 1 wk, and 4 wk after coronary ligation or sham operation. The animals were sedated with medetomidine and placed on a warm thermal plate. The stability of the body temperature was monitored with the use of a rectal probe. The echocardiographic measurements were performed with the use of a 12-MHz ultraband sector probe (SONOS model 5500, Hewlett-Packard; Andover, MA). LV systolic diameter and LV diastolic diameter (LVDD), respectively, were measured in the short-axis M-mode right parasternal projection in a plane below the mitral valves and perpendicular to the LV (27). An average of five measurements were used to measure LVDD and to calculate ejection fraction (EF). The coefficients of variation for repeated measurements of LV systolic diameter and LVDD were 0.027 and 0.046, respectively.
Histology and planimetry of infarct size. The presence of either signs of acute MI (eosinophilia, karyolysis, and leukocyte infiltration) or collagen scars compatible with an old infarction was analyzed by examination of Van Gieson-stained transverse LV sections. Infarct size was determined planimetrically as the ratio of infarcted tissue or scar to the length of the entire LV endocardial circumference as described previously (23). Infarcts were classified as small (4-30%), moderate (31-49%), or large (>50%). Hearts that showed no histological signs of infarction were not included in the study (n = 7).
Assessment of apoptosis. Apoptotic cardiomyocytes were detected with a terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) assay as previously described (6, 24, 25). In brief, myocardial tissue sections were heated in sodium citrate solution and digested with proteinase-K to expose the DNA. DNA strand breaks were labeled with the use of terminal transferase enzyme with dUTP molecules conjugated to alkaline phosphatase and visualized immunohistochemically. The assay was standardized with the use of serial sections treated with DNase I (1 U/ml for 30 min at 37°C) to induce the formation of DNA strand breaks (positive control of apoptosis). The development of the immunohistochemical staining was monitored by microscopy, and the reaction was interrupted at the moment when intense positive signal appeared in the corresponding DNase I-treated section (25).
Analysis of apoptosis was performed in one LV section obtained from the sample that showed maximal infarct size. The number of apoptotic cardiomyocytes was counted in the whole LV under light microscopy with an ocular grid. The cardiomyocyte origin of the apoptotic cells was identified by the presence of myofilaments surrounding the nucleus. The amounts of apoptotic cardiomyocytes were expressed as the proportion of the TUNEL-positive cardiomyocyte nuclei from the total number of cardiomyocyte nuclei, which was obtained by multiplying the density of cardiomyocyte nuclei in the serial DNase I-treated control section times the area of the section. The density of cardiomyocyte nuclei was always counted in at least four representative microscopic fields in each region of interest. To verify that all cardiomyocyte nuclei were labeled in DNase I-treated sections, we compared the nuclear densities obtained in DNase I-treated sections and Hoechst 33258-stained serial sections (n = 10). We did not find significant difference in the average nuclear density obtained with these two methods [887 ± 200 vs. 773 ± 98 (SD)]. The proportion of apoptotic cardiomyocytes was counted in the infarcted tissue, in the tissue bordering infarction (1-day infarctions), in the border zones of infarct scars (1- to 12-wk infarctions), and in the remote noninfarcted myocardium. The myocardium extending 0.5-1.0 mm from the infarcted tissue or infarct scar was considered to represent the border zone myocardium. To avoid contamination of the remote myocardium with border zones, a myocardial area extending ~1-2 mm from the border zone area was not included in the statistical analysis. The rest of the LV was considered to represent the remote myocardium. To assess the anatomical distribution of apoptotic cells quantitatively, we determined the relative proportions of the infarcted, border zone and remote myocardial regions of the total area of the LV in the analyzed section.Statistical analysis. Quantitative results were calculated as means ± SD. The differences in the amounts of apoptotic cardiomyocytes between groups were compared using one-way ANOVA and Bonferroni's method (SPSS Software; Chicago, IL). Echocardiography measurements between baseline and end point were compared in each group with the use of Student's t-test for paired data. Pearson's correlation coefficients were calculated to compare the amounts of TUNEL-positive cells and echocardiography measurements.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Myocardial infarction. Histologically, there was either an area of necrotic myocardium (day 1 after operation) or a collagenous infarct scar (1-12 wk after the operation) in 80% of the rats that underwent coronary artery ligation. Planimetrically, there were small, moderate, and large infarctions at a rate of 41, 28, and 31%, respectively. The sizes were equally distributed at all time points.
Cardiomyocyte apoptosis.
Apoptotic cells were rarely found in the sham-operated animals with
the use of the TUNEL assay. In contrast, after coronary artery
ligation, the apoptotic cells were much more numerous. TUNEL-positive inflammatory cells and interstitial cells were frequently observed in the infarcted areas 24 h after coronary ligation and among the scar tissue 1-12 wk after infarction. In contrast, very few scattered TUNEL-positive inflammatory or
interstitial cells were found in the border zones of infarct scars and
the remote myocardium. Also, TUNEL-positive cardiomyocytes were
numerous 24 h after coronary ligation in the infarcted tissue
(Fig. 1A). At later time
points, we observed scattered TUNEL-positive cardiomyocytes in the
border zones adjacent to infarct scars and in the remote myocardium
(Fig. 1, B and C), whereas they were absent among
the scar tissue. The TUNEL-positive cardiomyocytes contained condensed nuclei, which is a typical feature of cells undergoing
apoptosis (Fig. 1, A and B).
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Relative distributions of apoptotic cells in infarcted border
zone and remote areas.
To further analyze the quantitative distribution of apoptosis
in the remote, border zone and infarcted areas, we determined the
proportion of each region from the total area of the LV section. We
then calculated the distribution of apoptotic cells between these
areas. On day 1 after coronary artery ligation, most of the
TUNEL positivity occurred in the infarcted and border zone tissues (26 and 67% vs. 7% in the remote areas) (Fig.
3). Thereafter, the relative share of
apoptotic cells in the remote areas gradually increased to 37% in
1 wk (P < 0.01 vs. day 1), 54% in 4 wk
(P < 0.01 vs. day 1), and 70% in 12 wk
(P < 0.01 vs. day 1) after infarction.
Thus, although the percentage of apoptotic cells was higher in the
border zone areas, the remote areas dominated the actual amount of
apoptosis from week 4 after infarction.
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Apoptosis, ventricular function, and ventricular diameter.
To characterize the changes in ventricular function and geometry after
MI, we measured EF and LVDD with the use of echocardiography preoperatively and at 24 h, 1 wk, and 4 wk after the operation (Fig. 4). The sham-operated animals
showed only minor changes in EF during the study (Fig. 4A).
In contrast, EF decreased already 24 h after coronary occlusion
(63 vs. 51%, P = 0.01) and remained low thereafter.
Sham-operated animals did not show significant increases in the LVDD
(Fig. 4B). After coronary ligation, the ventricular
diameters were highly variable (from 7.5 to 11.1 mm). The average
ventricular diameter gradually increased and was 12% higher compared
with baseline at 4 wk after infarction (P = 0.01).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Occlusion of a major coronary artery in the rat is a well-characterized animal model of acute MI and its chronic sequelae, including congestive heart failure (19, 22, 23, 28). Previous studies in this model have shown that internucleosomal DNA fragmentation and TUNEL-positive cardiomyocytes can be found in the central ischemic areas in the acute phase of infarction (5, 13). Moreover, activated forms of caspases (2), the key executioners of apoptotic cell death, have been found in myocytes in this situation. Increased expression of the apoptosis-mediating Fas receptor (13) and increased ratio of a proapoptotic protein Bax to an antiapoptotic protein Bcl-2 have been suggested as potential mediators of myocyte apoptosis in this model (3).
On the basis of quantification of TUNEL positivity, apoptosis has been suggested to be the major form of cell death during the first hours of evolution of MI (5, 13). Apoptosis has also been found to a smaller extent in the viable myocardium of the LV free wall (3). In this area, apoptosis peaked on day 1 after infarction but continued at a low rate (0.02 apoptotic nuclei per 100 cardiomyocytes) until 4 wk after infarction (3). In contrast, the remote myocardium of interventricular septum showed constantly low rates of apoptosis (<0.01 apoptotic nuclei per 100 cardiomyocytes) (3). We extend the previous findings of Cheng et al. (3) by showing that the occurrence of cardiomyocyte apoptosis in the viable border zones of infarct scars remains high (5- to 12-fold compared with controls) even until 12 wk after experimental MI. Compared with sham-operated rats, apoptosis is also increased 2.5-fold in the entire remote noninfarcted tissue 24 h-4 wk after infarction. Moreover, we found that the amount of TUNEL-positive cardiomyocytes in the noninfarcted tissue correlated with the degree of ventricular enlargement, as measured with echocardiography at 1 and 4 wk after infarction. By 4 wk, as much as 54% of the TUNEL-positive cardiomyocytes resided in this large segment of the LV.
Significance of apoptosis in the acute stages of MI. As in previous human (12, 24) and experimental studies (1, 5, 8, 13), we found numerous TUNEL-positive cells in the infarcted and border zone regions on day 1 after infarction. The majority of the cells showed condensed nuclei, which is a typical feature of apoptosis (15). The significance of apoptosis compared with other types of cell death remains controversial in the acute stages of infarction. Only necrotic morphology of cell death has been found in two previous studies (8, 18) on acute ischemia-reperfusion. Moreover, a large proportion of TUNEL-positive myocytes have necrotic membrane damage, as demonstrated by uptake of myosin antibody from 6 h after coronary occlusion (13). A possible explanation for this could be that apoptosis and necrosis share common biochemical pathways in the early stages of the process (23). Apoptosis could even serve as a precursor of secondary necrosis (7, 15). In this study, we were interested in clarifying the role of apoptosis at later time points after infarction. At this time, only apoptotic inflammatory and interstitial cells were found among the infarct scars, whereas the apoptotic cardiomyocytes were observed at the border zone and remote areas.
Apoptosis and post-MI remodeling. Both experimental (3) and clinical studies (21) have shown that cardiomyocyte apoptosis is not limited to the acute stages of MI but remains increased in the viable myocardium adjacent to infarction. Ongoing cardiomyocyte apoptosis has also been shown to occur in areas supplied by partially occluded coronary artery in the human hibernating myocardium (4) and in experimental (26) and human ischemic chronic heart failure (17, 19, 25). Necrotic cardiomyocytes have not been found by anti-myosin labeling in the later stages of infarction in either border zones or remote areas (3). In the border zones of infarct scars, we did not find correlation between the amount of apoptosis and ventricular enlargement. This does not mean that apoptosis in these areas could not contribute to ventricular remodeling but that the process may be patchily distributed (24) and regulated dynamically by repetitive ischemia-reperfusion. Thus the kinetics of apoptosis may be such that the estimation of the total amount of apoptosis occurring in the time course is difficult on the basis of TUNEL-positivity quantified only at a limited number of time points.
In contrast to the border zone areas, we found that the amount of apoptosis in the remote myocardium correlated with an increase in the ventricular diameter 1 and 4 wk after infarction. This provides evidence that apoptosis in this region plays a role in post-MI ventricular remodeling and thus may contribute to the development of congestive heart failure. Actually, we calculated that by 4 wk after infarction the majority of apoptosis occurs in this region due to the large volume of the remote myocardium when compared with the border zone (Fig. 3). There are several possible triggers of apoptosis after MI in the remote myocardium. It has been proposed that stretch and tension of ventricular wall due to increased filling pressure could have caused apoptosis in rats with large infarctions (3). Notably,
-adrenoceptor blocking agents have reduced cardiomyocyte apoptosis in such experiments (31). In the present
study, the average size of infarction was moderate and did not cause
severe, progressive impairment of ventricular function, as measured
with echocardiography. The fact that there was no correlation between the amount of apoptosis and the decrease in EF may be partly
due to the technical limitations of assessing the overall function of
the ventricle with the use of single plane M-mode echocardiography.
Some paracrine mediators that are actively produced in the remote
myocardium after infarction in rats, such as tumor necrosis factor-
(11) and angiotensin II (10), have been shown
to induce cardiomyocyte apoptosis in vitro (14,
16). Recently, angiotensin-converting enzyme inhibitors have
been shown to decrease apoptosis in the border zones of infarct
scars in a dog model of ischemic heart failure
(9). However, the contributions of afterload reduction and
direct action on cardiac tissue angiotensin production to the
attenuation of remodeling by angiotensin-converting inhibitors remain
obscure (29).
In conclusion, we have shown that cardiomyocyte apoptosis
occurs after MI in the rat continuously over an extended period of time
both in the viable border zones of infarct scars and in the remote
noninfarcted myocardium. In the remote myocardium, apoptosis
correlates with ventricular enlargement and thus plays a role in the
postinfarction remodeling in this model.
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ACKNOWLEDGEMENTS |
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We thank Terhi Ilomäki for technical assistance and Hewlett-Packard (Espoo, Finland) for providing the ultrasound machine.
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FOOTNOTES |
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This study was supported by the Aarne Koskelo Foundation, Ida Montin Foundation, Finnish Heart Association, Finnish Cultural Foundation, Sigrid Jusélius Foundation, and by the clinical research funds of the Helsinki and Turku University Central Hospitals.
Address for reprint requests and other correspondence: L.-M. Voipio-Pulkki, Emergency Care, Dept. of Medicine, Helsinki Univ. Central Hospital, PO Box 340, FIN-00029 HUS, Finland (E-mail: liisa-maria.voipio-pulkki{at}hus.fi).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 23 November 1999; accepted in final form 23 January 2001.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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I. Bak, I. Lekli, B. Juhasz, N. Nagy, E. Varga, J. Varadi, R. Gesztelyi, G. Szabo, L. Szendrei, I. Bacskay, et al. Cardioprotective mechanisms of Prunus cerasus (sour cherry) seed extract against ischemia-reperfusion-induced damage in isolated rat hearts Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1329 - H1336. [Abstract] [Full Text] [PDF]
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D. Jegger, X. Jeanrenaud, M. Nasratullah, P.-G. Chassot, A. Mallik, H. Tevaearai, L. K. von Segesser, P. Segers, and N. Stergiopulos Noninvasive Doppler-derived myocardial performance index in rats with myocardial infarction: validation and correlation by conductance catheter Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1540 - H1548. [Abstract] [Full Text] [PDF]
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R. D. Patten, I. Pourati, M. J. Aronovitz, J. Baur, F. Celestin, X. Chen, A. Michael, S. Haq, S. Nuedling, C. Grohe, et al. 17{beta}-Estradiol Reduces Cardiomyocyte Apoptosis In Vivo and In Vitro via Activation of Phospho-Inositide-3 Kinase/Akt Signaling Circ. Res., October 1, 2004; 95(7): 692 - 699. [Abstract] [Full Text] [PDF]
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C. Depre, S.-J. Kim, A. S. John, Y. Huang, O. E. Rimoldi, J. R. Pepper, G. D. Dreyfus, V. Gaussin, D. J. Pennell, D. E. Vatner, et al. Program of Cell Survival Underlying Human and Experimental Hibernating Myocardium Circ. Res., August 20, 2004; 95(4): 433 - 440. [Abstract] [Full Text] [PDF]
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M. D. Schuster, A. A. Kocher, T. Seki, T. P. Martens, G. Xiang, S. Homma, and S. Itescu Myocardial neovascularization by bone marrow angioblasts results in cardiomyocyte regeneration Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H525 - H532. [Abstract] [Full Text] [PDF]
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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]
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A. Linke, W. Li, H. Huang, Z. Wang, and T. H. Hintze Role of cardiac eNOS expression during pregnancy in the coupling of myocardial oxygen consumption to cardiac work Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1208 - H1214. [Abstract] [Full Text] [PDF]
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M. N. Sharikabad, K. M. Ostbye, and O. Brors Increased [Mg2+]o reduces Ca2+ influx and disruption of mitochondrial membrane potential during reoxygenation Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H2113 - H2123. [Abstract] [Full Text] [PDF]
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J. M. Hare Oxidative Stress and Apoptosis in Heart Failure Progression Circ. Res., August 3, 2001; 89(3): 198 - 200. [Full Text] [PDF]
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