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Ann Thorac Surg 2007;84:1279-1287
© 2007 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Down-Regulation of Apoptosis After Left Ventricular Aneurysm Repair

Chiao-Po Hsu, MDa,b, Chun-Yao Huang, MDc, Jih-Shiuan Wang, MDa, Hsin-I. Chiang, MSa, Chun-Che Shih, MD, PhDa,b,*

a Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
b National Yang-Ming University, Institute of Clinical Medicine, Taipei, Taiwan
c Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan

Accepted for publication April 3, 2007.

* Address correspondence to Dr Shih, Division of Cardiovascular Surgery, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei, 112, Taiwan (Email: ccshih{at}vghtpe.gov.tw).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Apoptosis is a common feature of the cardiomyopathic process contriuting to progressive decline in ventricular function after transmural myocardial infarction. We hypothesized that left ventricular aneurysm repair (LVAR) down-regulates apoptotic potential of cardiomyocytes in the surviving myocardium.

Methods: In the rat infarct model, LV aneurysms were repaired by pursestring suture 2 weeks after coronary artery ligation. Cardiac function and myocardial infarction size were assessed by echocardiography and transverse heart sections, respectively, before sacrifice 12 weeks later. Cardiomyocytes and TdT-mediated dUTP terminal nick-end labeling (TUNEL) assays of apoptotic nuclei were analyzed adjacent to and remote from the aneurysm (8 in infarction group, 7 in aneurysm group, and 11 in repair group). Biochemical samples for immunoblot were also obtained from surviving myocardium.

Results: A statistically significant increase in apoptotic rate was seen in both adjacent and remote areas (p < 0.01) after aneurysm formation. After LVAR, heart function was improved, and TUNEL assays also show significant decrease when compared with aneurysm group. But significant decreases were noted only in activated caspase-9 and increases in Bcl-2 in immunoblot analysis when comparing repair group with aneurysm group.

Conclusions: Down-regulation of apoptosis accounts for the change in the long-term benefit after LVAR. To prevent heart failure, LVAR is indicated when it is large enough, and the infarction area should be excluded as much as possible.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Transmural myocardial infarction may result in the formation of a large dyskinetic aneurysm with progressive remodeling of the ventricles, ultimately leading to the development of left ventricular (LV) dysfunction and congestive heart failure. Medical therapy is typically ineffective, thus requiring surgical intervention. Surgical restoration of the LV aneurysm is widely accepted and has been carried out for decades. A large multicenter study was conducted to evaluate the results of surgical anterior ventricular endocardial restoration in patients with a dilated, remodeled left ventricle resulting from an anterior infarction [1]. The investigators documented good midterm results, with both clinical and functional improvements. Although the most appropriate surgical technique for LV aneurysm remains a debate, the diameter and size of the left ventricle, even wall tension, are always decreased after surgical restoration [2]. Up to now, the functional improvement after the repair of LV aneurysm is largely attributed to chronic unloading of the ventricular myocardium, which leads to better hemodynamic performance.

Loss of cardiomyocytes is a common feature of the cardiomyopathic process that contributes to progressive decline in LV function and congestive heart failure [3, 4]. Recent studies suggest that myocyte loss in cardiomyopathy can occur by apoptosis without an attendant inflammatory response [5]. Evidence also shows that myocyte apoptosis may play a role both in the pathogenesis and in the progression of the heart failure [5, 6]. Researchers have been able to detect apoptotic myocyte cell death and contraction and relaxation abnormalities, even in nonischemic zones remote from the aneurysm [7, 8].

Thus, we hypothesized that LV aneurysm repair might down-regulate apoptotic potential of cardiomyocytes. To test this hypothesis, we assessed the expression of apoptosis-related proteins, and TdT-mediated dUTP terminal nick-end labeling (TUNEL) stains in the surviving myocardium of rats with normal heart, and with aneurysms, both with and without repair.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Animals
Female Sprague-Dawley rats were used in this study. All experimental procedures were performed by experienced surgeons and cardiologist in accordance with the "Guidelines for Animal Experiments of Veterans General Hospital-Taipei," which conformed to the code of" Guide for the Care and Use of Laboratory Animals" in Taiwan.

Female rats were randomly allocated into three groups using the unbalanced complete random allocation method due to the higher incidence of mortality associated with myocardial infarction: 15 underwent thoracotomy only (group 1, sham operation); 25 with LV aneurysm underwent rethoracotomy only (group 2); and 32 with LV aneurysm underwent plication repair (group 3).

Myocardial Infarction
Rats weighing 190 to 240 g were subject to ligation of the left anterior descending coronary artery to produce a myocardial infarction, as described by Pfeffer and colleagues [9]. In summary, rats were anesthetized with enflurane, intubated, and ventilated with 1.5% to 2% enflurane in oxygen. Through left thoracotomy, left anterior descending coronary artery was ligated 2 to 3 mm from its origin about at the level of tip of left atrial appendage with a 7-0 polypropylene suture. The heart was returned to the chest, and the rib space and overlying muscles were closed. After recovery from anesthesia and extubation, the rats were returned to their cages. They were given water and standard rat food and housed in a climate-controlled environment with a 12-hour light and 12-hour dark cycle.

Left Ventricular Aneurysm Plication
Two weeks after myocardial infarction, rats were anesthetized and underwent a second thoracotomy, during which the heart was carefully dissected free of adhesions to visualize the extent of LV aneurysm. Rats whose myocardial infarction was not large enough visually were excluded from the study. Large LV aneurysms were identified and the apex of the heart was lifted to obtain a motionless operative field. A pursestring suture was created with 5-0 (round needle) polypropylene just onto the border line between infarcted and intact myocardium so that the infarct zone was excluded. Thereafter, the thoracotomy was closed, and the rats were allowed to recover.

Echocardiographic Studies
The echocardiographic studies were performed just before the sacrifice (12 weeks after the second operation). The rats were lightly anesthetized and placed in a supine position with pentobarbital, intraperitoneally (30 to 50 mg/kg) 30 minutes before examination. Using a commercially available echocardiographic machine equipped with a 7.5-MHz transducer (Hewlett-Packard), a two-dimensional short-axis view of the left ventricle was obtained at the level of the papillary muscles; and M-mode tracings were recorded through the anterior and posterior LV walls at a paper speed of 100 mm/s. Left ventricular anterior and posterior wall thickness, LV end-diastolic internal dimension (LVEDD) and LV end-systolic internal dimension (LVESD) were measured on the M-mode tracings. The percentage of fractional shortening (FS [%]) was calculated as: FS (%) = (LVEDD – LVESD) (x100%)/LVEDD.

All measurements were performed in a blinded fashion according to the recommendations of the American Society for Echocardiology, and averaged over five consecutive cardiac cycles.

Tissue Preparation
Tissue preparation is illustrated in Figure 1. After functional examination, a median sternotomy was performed to expose the heart and great vessels. For biochemical examination, the heart was harvested immediately and placed into ice-cold saline. A longitudinal incision was made along the axis from base to apex, the areas of the myocardial infarction or plication were excised, and the LV myocardium remaining was divided into eight segments. Four areas were identified as adjacent to the LV aneurysm or aneurysm repair and four as remote areas. These pieces were stored in liquid nitrogen. The left ventricles of the sham group were collected in the same manner.


Figure 1
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  		Fig 1. The method of tissue preparation for histologic examination (left) and biochemical examination (right). (A = adjacent; R = remote; S = scar.)

 
For histologic study, the right atrium was cut opened, and the ascending aorta was cannulated with an angiocatheter; the distal aorta was then clamped. High potassium solution was administered at 100 cm H2O by catheter to arrest the heart in diastole. Later, 50 mL 4% paraformaldehyde was infused through the coronary system to fix the heart at physiologic pressure. After removal of the atria and great vessels, the right ventricle (free wall) and LV (free wall plus septum) were blotted dry and weighed. The left ventricle was transversely sectioned into four segments and fixed in 4% paraformaldehyde in phosphate-buffered saline (pH 7.4), paraffin-embedded, and sectioned.

Left Ventricular Morphology and Morphometry
To elucidate the severity of myocardial scar, Masson’s trichrome staining was performed. Size of myocardial infarction was calculated as the percentage of circumference occupied by scar tissue similar to that of Pfeffer and coworkers [9]. Images were captured, magnified (x40), and merged together using a Zeiss microscope and Image-Pro Plus software.

Myocyte Size
Morphometric analysis of a cross-sectional area of cardiomyocytes was performed according to the method described by Camilión de Hurtado MC and colleagues [10], with 4-µm–thick tissue sections stained with hematoxylin and eosin. Sections from block 2 and block 4 represented adjacent and remote areas, respectively. Five random images obtained from each section were photographed under a microscope and magnified (x400). The magnitude of the cross-sectional area was the average of 100 cardiomyocytes, which were identified and manually traced with the computer to calculate the traced area using Image-Pro Plus software. To assess the cross-sectional area, only round to ovoid cells with visible round nucleus were considered. The operator was blinded to the experimental groups during the analysis.

TUNEL Assays
Cardiomyocyte apoptosis was quantified by the TdT-mediated dUTP terminal nick-end labeling (TUNEL) technique. The tissue sections from blocks 2 and 4 were treated with proteinase K, 20µg/mL (Roche Applied Science, Indianapolis, IN) after dewax and rehydration, then treated for 1 hour with the TUNEL reaction mixture containing TdT and fluorescein-dUTP at 37°C (In Situ Cell Death Detection Kit, Fluorescein; Roche Applied Science). Propidium iodide (0.5 mg/mL; Sigma, St. Louis, MO) was used as a counterstain. Positive controls were achieved by the treatment of DNase I (1µg/µL; Calbiochem, La Jolla, CA). The TUNEL-positive nuclei in the nonmyocardial infarction area were counted using fluorescence microscopy per section. Analysis of apoptotic rate was done as the method described by Olivetti and coworkers [7]. First, the next section for Masson’s trichrome stain was used for measuring the area of nonmyocardial infarction, namely, myocardial area examined for apoptosis (mm2). Six random images obtained from each section were photographed under a microscope and magnified (x400). The myocyte nuclear density (myocyte nuclei/mm2) was calculated from the total number of nuclei dividing by sum of myocardial area of these six images. The total number of nuclei of the myoctyes in the myocardial area examined for apoptosis was calculated. Then, the number of TUNEL-positive cardiomyocytes was divided by the total number of nuclei of myocytes to determine the ratio of TUNEL-positive myocyte nuclei.

Immunoblot
Nuclear and cytoplasmic protein extracts were prepared using NE-PER nuclear and cytoplasmic extraction reagents (Pierce Chemical, Rockford, IL) according to the manufacturer’s instructions. Protein concentration was determined using the Coomassie Plus Protein Assay Reagent Kit (Pierce Chemical).

Frozen protein lysates were thawed on ice and mixed with Laemmli sample buffer (Bio-Rad, Hercules, CA), and 5%-mercaptoethanol (Bio-Rad) while tested. Equal amounts (40 µg) of proteins were separated on 12% SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis; polyvinylidene difluoride) and electroblotted onto PVDF membrane. Nonspecific antibody binding sites were blocked by 5% nonfat milk containing 1X PBS-T buffer (PBS with 0.2% Tween-20) for 2 hours at room temperature. The membranes were incubated overnight at 4°C with the following primary antibodies: anticaspase-9 (monoclonal; Marine Biological Laboratory, Woburn, MA), anticaspase-8 (polyclonal; Chemicon, Billerica, MA), anticaspase-3 (polyclonal; Cell Signaling, Danvers, MA), anti-Bax (polyclonal; Neomarkers, Fremont, CA), anti–Bcl-2 (monoclonal; Marine Biological Laboratory), anti-PARP (monoclonal; Calbiochem), antiactin (monoclonal; Chemicon), and antitubulin (monoclonal; Sigma). Horseradish peroxidase–conjugated goat, anti-rabbit or sheep, and anti-mouse immunoglobulin (1:5,000) were used as secondary antibodies. The reactions were developed with enhanced chemiluminescence reagents (Amersham, Piscataway, NJ), and the images were obtained by exposure to x-ray films for anywhere from 10 seconds to 20 minutes. The films were digitized and quantified with the ImageQuaNT software (Molecular; Dynamics, Sunnyvale, CA). To allow for comparison between the groups, data are shown as percent density of bands versus corresponding samples of sham group.

Statistical Analysis
For statistical analysis, the software SPSS 10.0 for Windows (SPSS, Chicago, Illinois) was used. All values are expressed as mean ± SD. The differences in the data between the two groups were determined by a Student’s t test. Comparison between all groups was assessed by one-way analysis of variance followed by Bonferroni’s post-hoc test. A p value less than 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Mortality
Mortality rates of groups 1, 2, and 3 were 0 of 15, 7 of 25, and 8 of 32, respectively, after the first operation; and 1 of 15, 3 of 18, and 4 of 24, respectively, after the second operation. Of the surviving rats, 2 in group 2 and 3 in group 3 whose aneurysms were not large enough were excluded from the study. The final 44 rats were used for analysis and formed the basis of this study, 26 for histologic study and 6 in each group for biochemical study. Select characteristics are summarized in Table 1.


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  		Table 1 Effect of LV Aneurysm and Its Plication on Ventricular Weight, Measurements Checked by Echocardiography, and Histologic Analysis 12 Weeks After Aneurysm Repair
 
Weight Changes
At 12 weeks after the second operation, body weight change, left ventricular, right ventricular, and biventricular weight ratio were not statistically different among the three groups (p > 0.05, Table 1).

Echocardiography
Results from the echocardiography study are also summarized in Table 1. There were no differences in heart rate and posterior wall thickness among the three groups. However, anterior wall thickness, left ventricular end-systolic diameter, left ventricular end-diastolic diameter, and fractional shortening were statistically significantly different between groups 2 and 3, and there was no statistically significant difference seen between groups 1 and 3.

Cardiac Geometry and Scar Length
Representative transverse heart sections with Masson’s trichrome stain are provided in Figure 2. The myocardial infarction area is stained in blue. The infarction area ratio was reduced and wall thickness over the myocardial infarction area increased after plication (p < 0.001 in Table 1).


Figure 2
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  		Fig 2. Masson’s trichrome–stained transverse heart sections from group 2 (left) and group 3 (right). Plication of aneurysm scar in the left ventricle resulted in a smaller, thicker (less dilated) left ventricular chamber. Photographs are printed directly from representative slide sections cut from the apex through the base at level 1 (A and E), level 2 (B and F), level 3 (C and G), and level 4 (D and H). Images were captured, magnified (x40), and merged together using a Zeiss microscope and Image-Pro Plus software. (Scale bar = 1 mm.)

 
Cardiomyocyte Size
The cross-sectional area of cardiomyocytes was significantly increased after LV aneurysm formation, and significantly decreased after aneurysm repair irrespective of area. Meanwhile, the cross-sectional areas in the remote areas were smaller than that seen in the adjacent areas (Fig 3). Representative sections of adjacent areas in group 2 and the remote areas in group 3 are provided in Figure 4.


Figure 3
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  		Fig 3. Cross-sectional area of cardiomyocytes in the surviving portion of the left ventricle. Results are presented as mean ± SD. (A = adjacent area; R = remote area.)

 

Figure 4
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  		Fig 4. Representative sections of (A) adjacent area of group 2 and (B) remote area of group 3. Cross-sectional area in A is obvious larger than in B. Magnification x400. (Scale bar = 50 µm.)

 
Cardiomyocyte Apoptosis
From TUNEL assay of cardiomyocyte nuclei (Fig 5), we calculated the apoptotic rate significantly increasing from 5.1 ± 1.7 to 23.9 ± 6.7/104 nuclei in the adjacent area, and from 4.4 ± 1.6 to 11.1 ± 1.3/104 nuclei in the remote area after LV aneurysm formation. Through aneurysm repair, only 11.6 ± 1.3 and 6.9 ± 1.1/104 nuclei were positive for TUNEL in the adjacent and remote area, respectively, a statistically significant decrease compared with group 2. We also found that the apoptotic rate in the remote area was significantly less than that in the adjacent area in groups 2 and 3 (Fig 6).


Figure 5
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  		Fig 5. Apoptosis of myocyte in the adjacent area of ventricular myocardium of group 2 (A, B, C) and group 3 (D, E, F). Red fluorescence illustrates nuclei by propidium iodide (PI) (A and D) and green fluorescence illustrates apoptotic nuclei by the terminal deoxynucleotidyl transferase (TdT) assay (B and E). Fluorescence in C and F corresponds to the combination of PI and TdT labeling, fluorescence microscopy. Magnification x400. (Scale bar = 50 µm., Fremont, CA)

 

Figure 6
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  		Fig 6. Effects of left ventricular aneurysm and aneurysm repair on the magnitude of apoptosis of cardiomyocyte in the surviving portion of the left ventricle. Results are presented as mean ± SD. (Open bars = adjacent; shaded bars = remote.)

 
Immunoblot
To determine whether the decrease in cardiomyocyte apoptosis rate in the group 3 was accompanied by a change of the proteins associated with apoptosis, immunoblot analyse of activated apoptosis-related proteins was conducted. Results are shown in Figure 7. A significant decrease was noted in activated caspase-9 in the adjacent (35kD and 37kD) area when comparing group 3 with group 2. Bax, activated caspase-8 (43kD), and caspase-3 also decreased, although they did not reach statistical significance in the corresponding areas. A significant increase of Bcl-2 was noted in the adjacent area of group 3 compared with group 2. The expression with Bcl-2/Bax was more notable, which demonstrated statistically significant increase in the remote area (p < 0.005), but did not reach significance in the adjacent area.


Figure 7
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  		Fig 7. (Left) Representative immunoblots for caspase-8(43kD), Bcl-2, caspase-9 (35 and 37kD), Bax, caspase 3, {alpha}-tubulin, and actin. (Right) Laser densitometry data (n = 6 in each group, mean ± SD). (A = adjacent area; LVA = left ventricular aneurysm; LVAR = left ventricular aneurysm repair; R = remote area.)

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Left ventricular aneurysm repair has been used as an accepted therapy for LV aneurysm for decades. Although LV aneurysm repair has been shown to effect salutary changes in myocyte function, myocardial remodeling, and LV geometry [2, 11], the cellular and molecular mechanisms responsible for alterations in the heart failure phenotype remain undefined.

With prolonged cardiovascular stress or pathophysiologic stimuli, the myocardium undergoes a cascade of compensatory structural events, namely, the remodeling process. The remodeling process is complex and may involve LV hypertrophy, dilation, the renin-angiotensin-aldosterone system, the sympathetic nervous system, and alterations in intracellular calcium homeostasis. These mechanisms are closely associated with heart failure and are considered potent inducers of apoptosis [12]. In an in vitro study, overstretching of cardiomyocytes, such as occurs with LV aneurysm, can also result in upregulation of the local renin-angiotensin system [13] and reactive oxygen species [14], which increase the susceptibility of myocytes to undergo apoptosis.

Apoptosis in heart failure has been established in animal and human studies [5, 6]. The number of apoptotic cells is significantly lower in heart failure than in ischemic myocardial conditions, making the investigation of cardiomyocyte apoptosis in congestive heart failure a difficult task. It is difficult to differentiate the magnitude of the apoptotic rate of cardiomyocytes from tissue sections under fluorescence microscopy. Using the method described by Olivetti and coworkers [7], we did note an increase in the apoptotic rate after LV aneurysm formation and a decrease in the apoptotic rate after surgical repair. The up-regulation of apoptosis after LV aneurysm can thus be improved by aneurysm repair.

We used enhanced chemiluminescence reagents and increased exposure times to x-rays for the activated forms of apoptosis-related proteins in our study, and have demonstrated that the quantity of activated proteins was comparatively low. This evidence also supports the observation of lower numbers of apoptotic cells in the TUNEL assay. We also found the density of proteins in the mitochondrial pathway (caspase-9, Bax, and Bcl-2) was greater than that in the death receptor pathway (caspase-8), implying that the death receptor pathway plays a secondary role in cardiomyocyte apoptosis, which was demonstrated by Kubota and colleagues [15]. In our study, not all of protein densities reached significance when comparing adjacent or remote areas between groups 2 and 3. However, if we regarded the adjacent and remote areas together, and conducted a between-group analysis (groups 2 and 3), caspase-8 (43kD), Bcl-2, Bax, caspase-9 (35kD and 37kD), and Bal-2/Bax, but not caspase-3, reached statistical significance. These results are due to the small quantity of proteins and the semiquantitative properties of the immunoblot; more sophisticated techniques, such as enzyme-linked immunosorbent assay or radioimmunoassay, may have greater sensitivity. Activated caspase-3 was assessed using fluorescence immunohistochemistry, confirming that apoptosis occurred in the cardiomyocytes (Fig 8).


Figure 8
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  		Fig 8. Fluorescence immunohistochemistry of activated caspase-3 from (A) group 2 and (B) group 3. Tissue sections were treated with 3% H2O2 and blocked with 1% nonfat milk in phosphate-buffered saline-T buffer after dewax and rehydration. Binding of primary probe with antiactive caspase-3 antibody (polyclonal, Chemicon), followed by biotin-labeled secondary goat anti–rabbit IgG antibody (Invitrogen). Higher levels of signal amplification were achieved by Tyramide Signal Amplification Kit (T20932, Alexa Fluor 488; Invitrogen), and counterstained with DAPI (4'-6-Diamidino-2-phenylindole). Magnification x400. (Scale bar = 50 µm.)

 
The expression of some proteins (caspase-8, caspase-9, and Bax) in group 3 was unexpectedly lower than in group 1, which did not agree with the results from the TUNEL assay. There may be other regulatory proteins involved in apoptosis; alternatively, other mechanisms, such as the activity of the sympathetic nervous system or the renin-angiotensin-aldosterone system may affect the expression of apoptosis. The ratio between Bcl-2 and Bax in cardiomyocytes has been shown in human and animal studies to be related to the magnitude of apoptosis [16], which was confirmed by the results herein.

Cardiac remodeling after transmural myocardial infarction is also associated with cardiomyocyte hypertrophy within the remaining viable myocardium. This process involves an increase in myocardial mass, primarily by means of the serial addition of new sarcomeres and fiber elongation without relative wall thickening and resulting in chamber enlargement [17]. The mechanisms of cardiac muscle hypertrophy involve many signal transduction pathways, leading to the induction of a number of genes, which in turn stimulate synthesis of numerous cellular proteins [18, 19]. In a report by Sakaguchi and associates [20], reduction of up-regulation of fetal and adult contractile protein associated with cardiac hypertrophy was demonstrated after plication of a LV aneurysm. We also found that hypertrophy of cardiomyocytes was improved after LV aneurysm repair, and the more remote the cardiomyocytes, the less the hypertrophy.

In our model, we noted there was an 8.9% infarction area after LV aneurysm repair, which may be another important reason that statistical significance was not reached in some coparisons. However, from the trends observed in our study, the repair of a LV aneurysm with exclusion of as much of the infarction area as possible remains a sound therapy. The method of the LV aneurysm repair may not be as important as the effect of downsizing. Further investigations defining the molecular consequences after LV aneurysm repair are necessary.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
The assistance of Ching-Ya Hsu is greatly appreciated. This work was supported by grants from the National Science Council, Taiwan NSC-95-2341-B-010-028-MY3 and 94-2314-B-010-057; Taipei Veterans General Hospital, Taiwan V95C1-049, V95E1-010, V95ED1-008, V95-S22-005; and Research Foundation of Cardiovascular Medicine (94-01-007), Taipei, Taiwan.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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  2. Savage EB, Downing SW, Ratcliffe MB, et al. Repair of left ventricular aneurysmChanges in ventricular mechanics, hemodynamics, and oxygen consumption. J Thorac Cardiovasc Surg 1992;104:752-762.[Abstract]
  3. Beltrami CA, Finato N, Rocco M, et al. The cellular basis of dilated cardiomyopathy in humans J Mol Cell Cardiol 1995;27:291-305.[Medline]
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  9. Pfeffer MA, Pfeffer JM, Fishbein MC, et al. Myocardial infarct size and ventricular function in rats Circ Res 1979;44:503-512.[Abstract/Free Full Text]
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  16. Koglin J, Granville DJ, Glysing-Jensen T, et al. Attenuated acute cardiac rejection in NOS2 -/- recipients correlates with reduced apoptosis Circulation 1999;99:836-842.[Abstract/Free Full Text]
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