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Ann Thorac Surg 1999;68:301-307
© 1999 The Society of Thoracic Surgeons
a Division of Cardiothoracic Surgery, McGill University, Montreal, Canada
b Department of Pathology, McGill University, Montreal, Quebec, Canada
Address reprint requests to Dr Chiu, Division of Cardiothoracic Surgery, Room C9.169, Montreal General Hospital, 1650 Cedar Ave, Montreal, PQ H3G 1A4, Canada
e-mail: mdiu{at}musica.mcgill.ca
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Abstract |
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 Top Abstract TSDA Resident Research AwardIntroduction of Dr Chu...Material and methodsResultsCommentReferences |
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Methods. Ameroid constrictors were implanted around proximal circumflex arteries of porcine hearts. Six weeks later, they were randomly assigned (n = 5 each) to receive 10 transmural channels in the ischemic zone by a carbon dioxide laser (group I) or by a needle (group II). A third group (group III) had 30 needle channels in the same area, while a control group (group IV) received no TMR. The hearts were harvested 1 week later, and, using immunohistochemistry, vascular endothelial growth factor (VEGF) expression was studied and quantified by computerized morphometric analysis. Densities of vascular structures positively stained for VEGF per high-power field (HPF) were also compared.
Results. Virtually no TMR channels remained patent histologically. Group III had a significant higher level of total VEGF expression (14.18 ± 0.78 mm2) compared with group I (7.07 ± 2.06 mm2, p < 0.001) and group II (4.74 ± 3.35 mm2, p < 0.001). Vascular density was significantly elevated in all treatment groups compared with the control (group I, 7.7 ± 0.8/HPF vs group II, 4.5 ± 2.3/HPF vs group III, 8.1 ± 0.6/HPF vs group IV, 1.1 ± 0.5/HPF).
Conclusions. In view of the significant cost implications, our findings that needle punctures may also induce angiogenic response comparable with that with laser suggest that it is justifiable and desirable to include a TMMR arm for comparison with TMLR in future clinical trials.
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TSDA Resident Research Award |
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TopAbstractTSDA Resident Research AwardIntroduction of Dr Chu...Material and methodsResultsCommentReferences |
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The ninth TSDA Resident Research Award was given to Victor F. Chu, MD, a cardiac surgery resident in the Department of Surgery, McGill University, Montreal, Quebec, Canada, who is completing a thoracic surgery research Fellowship in the Department of Surgery. He received a monetary award of $2,500 and an engraved desktop award.
The TSDA, with support by Medtronic, Inc, makes this award annually, using the above selection procedure. The resident author of the selected study is recognized at the STS meeting.
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Introduction of Dr Chu by TSDA President Mark B. Orringer |
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TopAbstractTSDA Resident Research AwardIntroduction of Dr Chu...Material and methodsResultsCommentReferences |
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The idea for this award originated in 1987 with Mr Earl Bakken, founder of Medtronic, Inc, and it was developed in subsequent discussions with Benson Wilcox. The intent of this award was to encourage research in cardiothoracic surgery. The award was first presented in February 1991 at the TSDA meeting which preceded the STS meeting. Medtronic has provided monetary sponsorship of the award, which includes a check in the amount of $2,500 to the resident, and granite desk awards to both the resident and his or her program director/mentor which are presented both at the TSDA meeting and at one of the plenary sessions of the STS.
As president of the TSDA, I’m pleased to present this year’s TSDA Residents Research Award to Dr Victor Chu of Montreal General Hospital and McGill University in Montreal for his abstract entitled "Angiogenic Response to Transmyocardial Revascularization (TMR): Laser Versus Mechanical Punctures." This work was performed in the thoracic surgery research laboratory there, where Ray C.J. Chiu is the program director. Let me also note that this is the second consecutive year in a row that this program director, Dr Chiu, has had a resident from his laboratory win this award, and it says a great deal for the caliber and the quality of the work.
So congratulations to our winning resident, Victor Chu, and to our program director, Dr Chiu.
Transmyocardial revascularization (TMR) is a novel surgical procedure aimed at restoring myocardial perfusion by creating transmural channels in areas of schemic but viable myocardium. Recently, several clinical trials [1] have shown that TMR can effectively reduce angina symptoms in patients with end-stage coronary artery diseases who have exhausted other treatment alternatives. However, the mechanisms by which TMR achieves its therapeutic effects as well as the optimal methods of creating transmural channels are still undetermined.
An initial "open channel" hypothesis suggested that TMR improves myocardial perfusion by establishing direct connections of left ventricle to the myocardial sinusoidal system through patent transmural channels [2]. Since laser-created channels are thought to be more likely to remain patent than needle punctures [3], laser TMR became the preferred method in recent years. However, a growing body of evidence suggests that laser channels did not remain open and that TMR could achieve treatment benefits without long-term channel patency.
These apparent discrepancies and other observations have led some to hypothesize that TMR induces angiogenesis and improves myocardial collateral circulation through a tissue injury/wound-healing process. It is well known that during the inflammatory and proliferating phases of wound healing, there is significant upregulation of various growth factors in order to promote angiogenesis and neovascularization. Previous studies in this laboratory [4] as well as by others have shown that TMR using both needle and laser was associated with significantly elevated angiogenic growth factor expression and vascular densities in treated areas. However, little is known about the relative efficacy in promoting tissue angiogenesis by these two different techniques.
To address this question, we compared mechanical TMR using 18-gauge hypodermic needles with carbon dioxide (CO2) laser TMR by measuring the expression of vascular endothelial growth factor (VEGF) and VEGF-induced angiogenesis in a chronically ischemic porcine model.
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Material and methods |
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TopAbstractTSDA Resident Research AwardIntroduction of Dr Chu...Material and methodsResultsCommentReferences |
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Animal model with chronic ischemia
Twenty-three Yorkshire pigs weighing 15 to 20 kg were premedicated with intramuscular ketamine (15 mg/kg) and were anesthetized with intravenous injection of thiopental sodium (15 mg/kg). After oral endotrachial intubation, anesthesia was maintained with 0.5% to 2.0% isoflurane in room air. Oxygen saturation was continuously monitored using a transcutaneous oxymeter probe. Five hundred milligrams of cefazolin was given intravenously before skin incision.
Animals were placed in a right lateral decubitus position. The thorax area was prepared and draped in a sterile fashion. Exposure of the proximal left circumflex artery (LCx) was achieved via a mini thoracotomy through the fourth intercostal space. A 1-cm segment of LCx before the first obtuse marginal branch was dissected free using both sharp and blunt dissections. Care was taken to minimize direct manipulation of the artery itself to avoid vessel spasm. An ameroid constrictor (2.75 mm; Research Instruments, Corvallis, OR) was placed around LCx. The pericardium and the chest were closed in layers and the anesthesia was reversed. The animals were kept for 6 weeks to allow time for gradual occlusion of the LCx artery by ameroid constrictors.
Transmyocardial revascularization
At 6 weeks after the insertion of ameroid constrictors, the 20 surviving animals were randomly assigned to four groups (n = 5 each). Group I received 10 laser punctures, group II received 10 needle punctures, and group III received 30 needle punctures, all within the same ischemic area. A control group (group IV) underwent sternotomy only.
All TMR operations were performed through median sternotomy. Anesthesia and intubation were performed in the same fashion as the first operation. All animals received prophylactic intravenous xylocaine bolus (2 mg/kg) and were maintained on xylocaine infusion (1 mg/min) throughout the operation. Median sternotomies were performed and the hearts exposed by opening the pericardium and carefully dissecting away pericardial adhesions. Transmural punctures were created in an area measuring approximately 2 x 2 cm between the first and second obtuse marginal arteries using either CO2 laser (UltraPulse 5000C; Coherent Inc, Palo Alto, CA) or 18-gauge hypodermic needles. Laser power output was set at 100 W, laser beam diameter was 0.2 mm, and laser pulse duration was 20 ms. Transmural punctures were confirmed by noting pulsatile bleeding of arterial blood from laser holes or through the needle. Bleeding was controlled with 4-0 prolene sutures, which also served as markers of puncture sites at the time of tissue harvest. Sternums were then closed with steel wires and the incisions closed in layers. Anesthesia was reversed and the animal allowed to recover.
Sample harvest and cryopreservation
One week after TMR, repeat sternotomies were performed through the same incision. Hearts were isolated by careful dissection of adhesions. Animals were killed with an overdose of pentobarbital and potassium chloride. The ascending aortas were cross-clamped and the hearts fixed in situ by injecting 1 L of ice-cold 4% paraformaldehyde through aortic root. Full-thickness slices of myocardium from the TMR-treated area (or corresponding ischemic area in the control group) were removed and immediately immersed in 4% paraformaldehyde in phosphate-buffered saline (PBS). These were kept at 4°C for 12 hours. The specimens were then transferred into 15% sucrose in PBS and kept at 4°C for 3 days. Afterwards, samples were embedded in OCT compound (Tissue-Tek; Sakura Finetek Inc, Torrance, CA) and snap-frozen with liquid nitrogen and kept at -80°C.
All ameroid constrictors were retrieved from the heart and inspected to confirm vessel occlusion.
Sample analysis
Immunohistochemistry
Cryostat sections of tissue samples were mounted on glass slides and immunostained with antisera to VEGF ligands (Santa Cruz Biotechnology Inc, Santa Cruz, CA) with a modified avidin biotin-peroxidase method [5]. Tissue sections were made permeable with triton X-100, and incubated in hydrogen peroxide to block endogenous peroxidase activity. They were then incubated first with normal goat serum for 30 minutes and followed with the primary antibody for 16 hours at 4°C. Afterwards, they were incubated with biotinylated immunoglobulin G and stained with an immunoperoxidase technique according to the manufacturer’s instructions (Vectastain ABC Elite Kit; Vector Laboratories, Burlingame, CA).
Angiogenic growth factor expression
Growth factor expression was quantified by measuring the area of tissue sections positively stained for VEGF in each high-power field (HPF; 400x). Measurements were performed around TMR puncture sites, which were identified by the following criteria: (1) identifiable needle or laser tracks under low-power view (LPV; 100x), (2) presence of inflammatory cells and granulation tissue, and (3) loss of normal myocyte appearance and homogeneity. Using the sampling method of "systematic sampling with a random start" [6], eight sampling sites from each tissue section were photographed with a still video camera and digitized into tagged image file format (TIFF) files. Quantitative measurements of stained area were performed with an IBM-compatible personal computer using Matrox Inspector 2.1 (Matrox Inc, Montreal, Canada). Total amount of VEGF expression for each animal were reported as mean area of VEGF stain (mm2) per HPF x number of punctures.
Vascular density
TMR-induced angiogenesis was quantified by measuring vascular density of VEGF-stimulated blood vessels per HPF around puncture sites. VEGF-stimulated vessels were defined as round structures with a central lumen, which was lined by a thin layer of endothelium stained positively for VEGF. Eight measurements were taken for each tissue section using the same sampling method. Results of angiogenesis for each animal were reported as mean number of vessels per HPF.
Statistical analysis
Results are reported as mean ± 1 standard deviation where applicable. Data were analyzed with Student’s t test using SPSS 7.5.2 for Windows (SPSS Inc, Chicago, IL). A p value of less than 0.05 was considered significant.
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Results |
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TopAbstractTSDA Resident Research AwardIntroduction of Dr Chu...Material and methodsResultsCommentReferences |
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One animal developed ventricular fibrillation during laser punctures and required electrical defibrillation. This animal completed the study without further complications. Two animals in laser TMR group (group I) were noted to have significant hemothorax at time of organ harvesting, although this was not apparent clinically.
Histology
In both laser- and needle-treated specimens, the areas of transmural punctures were easily identified by the presence of numerous fibrous scars on the endocardium. Laser scars were considerably larger, measuring 1–3 mm, compared with needle scars, which were pinpoint in sizes. All animals had complete occlusion of LCx at the time of sample harvesting (7 weeks after ameroid insertion).
Under low-power light microscopic examinations, laser sites could be identified as central fibrous tracts surrounded by characteristic inflammatory changes consistent with laser injuries. There were no identifiable patent laser channels. The fibrous tracts, which consisted mainly of fibroblasts and collagen material with occasional small blood vessels, were narrower than the laser beam diameter (0.2 mm) used in our study. The surrounding area consisted of granulation tissue and damaged myocardium with infiltrating lymphocytes and macrophages. These were similar to the typical inflammatory changes during normal tissue healing process. Numerous small vascular structures were also found in the area of tissue inflammation. These vessels were morphologically indistinguishable from native myocardial capillaries except for their endothelium, which was positively stained for VEGF (see Fig 3A). Most of these vessels were smaller than 10 µm in diameter and were believed to be at various stages of angiogenic development.
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TMR-related tissue injuries and inflammation in all three treatment groups were limited to the immediate vicinity of myocardial punctures. Each puncture site was separated from others by normal-looking myocardium indistinguishable from control specimen under light microscopy.
VEGF expression
Several cell types stained positively for VEGF, including endothelial cells, macrophages, fibroblasts, as well as myocytes. In all treatment groups, positive stains were limited to the puncture sites and adjacent areas. In general, endothelium and macrophages gave the most intense stains but represented only a small portion of the total area as measured by computer-assisted morphometry. On the other hand, myocytes and fibroblasts produced a more diffused staining pattern and represented most of our measurements for VEGF expression (Fig 1). Very few stains were present in areas away from puncture sites, and measurements from these areas were not significantly higher than the baseline.
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Comment |
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TopAbstractTSDA Resident Research AwardIntroduction of Dr Chu...Material and methodsResultsCommentReferences |
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During the past two decades, all clinical studies of TMR involved the use of specially designed laser devices. Although Sen and associates used needle myocardial acupuncture in their original studies of the "snake heart operation" [2], little attention was given to this simple mechanical TMR technique. Major criticisms of needle TMR were centered around the observation that needle tracts were obliterated early in the postoperative period as a result of thrombosis and inflammatory cellular infiltration. When Mirhoseini and colleagues [7] pioneered laser transmyocardial revascularization, they suggested that the laser, more specifically a high-power CO2 laser, has unique physical characteristics promoting channel patency. However, numerous more recent histological and pathological studies did not support long-term patency of laser channels [8–12]. Furthermore, since TMR appears to be able to achieve angina relief without evidence of direct transmyocardial blood flow, the question of channel patency is no longer regarded as a key issue as it used to be. Although the laser did not achieve its original mandate, ie, maintaining channel patency, it was instrumental in generating public interest during the developmental stage of TMR by providing an aura of high technology to the decade old "snake heart operation." It is also industry driven, receiving enthusiastic support from laser companies.
One of the consistent findings from different TMR studies was the presence of significant inflammatory responses in the vicinity of myocardial punctures [9, 12–14], not unlike that seen in a usual wound healing process. It is well known that angiogenesis and neovascularization play a central role during the initial phases of wound healing [15]. This angiogenic response is stimulated by various growth factors released as a result of tissue injury and inflammatory cellular infiltration. The end result is seen as increased vascular density in the injured area. If one were to consider TMR simply as a way of creating injury, then it is logical to expect that an inflammation-mediated angiogenic response could also occur in the myocardium. In the ischemic heart, TMR-induced angiogenesis leads to the formation of collateral circulation and improves myocardial perfusion.
Several observations from our study are consistent with such an angiogenic mechanism. At 1 week after the TMR procedure, both laser and needle puncture groups had intense inflammatory reactions surrounding myocardial puncture sites. The involved areas were limited to the vicinity of TMR channels. Laser TMR was associated with noticeably larger areas of inflammatory changes. This could be explained by the fact that laser punctures created more extensive tissue injuries than needles. While injuries from needle punctures were limited to areas immediately adjacent to the needle track, the laser caused a zone of thermal injury in addition to tissue ablation. Such differences in tissue reactions had been reported in previous studies comparing needles with different types of lasers [16]. More extensive tissue injury could explain why individual laser channels showed a trend towards higher VEGF expression on a per-channel basis, although the difference did not reach statistical significance. However, morphological and immunohistochemical changes from these different TMR methods are fundamentally similar. The difference between laser and needle punctures is merely quantitative, not qualitative. This is easy to understand, since inflammatory reactions triggered by tissue injury are the common pathway leading to angiogenic response, thus, any difference in angiogenesis reflects the extent rather than the type of tissue injuries.
One important finding in our study was that increased VEGF expression was limited to a small area adjacent to the puncture sites. Therefore, the total amount of VEGF would depend on the number of punctures created. By making three times as many needle punctures in group III, we were able to achieve a higher level of angiogenic factor expression than in the laser group.
VEGF is a potent direct stimulant of neovascularization and vessel proliferation with receptors on the endothelial cells. We found significantly higher number of developing vessels with VEGF-stained endothelium in TMR-treated groups. We postulate that these were newly formed vessels stimulated by locally secreted VEGF. Comparing vessel density among different treatment groups revealed that higher level of growth factor expression correlated with higher number of positively stained vessels. By increasing the number of punctures, needle TMR was able to be equally effective in inducing neovascularization when compared with laser TMR.
TMR angiogenesis occurs at the expense of myocardial injury. When comparing different TMR methods, one must take into consideration the issue of TMR "efficiency," which could be defined as the magnitude of angiogenesis achieved with a given amount of muscle destruction. An ideal method would yield a high level of angiogenesis with minimum damage to the myocardium. Whether a simple mechanical trauma from needle puncture or a more complex laser thermal injury is more "efficient" in creating angiogenesis remains to be clarified by future studies.
Our present study employed a general-purpose laser machine with a maximum power output less than what is commonly used clinically. We compensated for this by decreasing the laser beam diameter and increasing the density of laser punctures. In fact, the laser beam power density in our study was 3200 W/mm2, higher than the 1275 W/mm2 delivered by the HeartLaser. Transmural puncture was achieved instantaneously without any difficulty.
In summary, this study directly compared mechanical needle punctures against CO2 laser by measuring TMR-induced angiogenesis and neovascularization. In our study, mechanical TMR could be as effective as CO2 laser TMR in stimulating VEGF expression. Although individual laser puncture was more effective in increasing myocardial vascular density, such difference was qualitative and was fully compensated with higher number of needle punctures.
Two questions remain to be answered by this study. What is the fate of TMR-induced vessels? And what is the functional significance of these vessels? Future studies, including a time-course assessment of vascular development after TMR, and functional and perfusion studies of TMR-treated myocardium, would help to answer these questions.
Recent clinical trials and advances in TMR technology received powerful support and valuable contributions from the laser industry. However, in view of the significant cost implication, we believe that our findings of needle punctures capable of inducing angiogenic response comparable with that with laser suggest that it is justifiable and may be desirable to include mechanical TMR for comparison with laser TMR in future clinical trials.
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Acknowledgments |
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References |
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TopAbstractTSDA Resident Research AwardIntroduction of Dr Chu...Material and methodsResultsCommentReferences |
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