ARTICLE
Transmyocardial revascularization with CO2 laser in patients with refractory angina pectoris
Clinical results from The Norwegian Randomized Trial
Lars Aaberge, MDa,
Kenneth Nordstrand, MD, PhDb,
Morten Dragsund, MDb,
Kjell Saatvedt, MD, PhDb,
Knut Endresen, MD, PhDa,
Svein Golf, MD, PhDb,
Odd Geiran, MD, PhDa,
Michel Abdelnoor, MPH, PhDa and
Kolbjorn Forfang, MD, PhDa
a Division of Heart and Lung Diseases, The National Hospital, University of Oslo, Oslo, Norway
b The Feiring Heart Clinic, Feiring, Norway
Manuscript received July 9, 1999;
revised manuscript received October 25, 1999,
accepted December 15, 1999.
Reprint requests and correspondence: Dr. Lars Aaberge, Department of Cardiology, Rikshospitalet, N-0027 Oslo, Norway
laaaberg{at}online.no
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Abstract
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OBJECTIVES
The purpose of the study was to evaluate clinical effects, exercise performance and effect on maximal oxygen consumption (MVO2) of transmyocardial revascularization with CO2-laser (TMR) in patients with refractory angina pectoris.
BACKGROUND
Transmyocardial laser revascularization is a new method to treat patients with refractory angina pectoris not eligible for conventional revascularization. Few randomized studies comparing TMR with conventional treatment have been published.
METHODS
One hundred patients with refractory angina not eligible for conventional revascularization were block-randomized in a 1:1 ratio to receive continued optimal medical treatment (MT) or TMR in addition to MT. The patients were evaluated at baseline and at three and 12 months with end points to symptoms, exercise capacity and MVO2.
RESULTS
Transmyocardial laser revascularization resulted in significant relief in angina symptoms after three and 12 months compared to baseline. Time to chest pain during exercise increased from baseline by 78 s after three months (p = NS) and 66 s (p < 0.01) after 12 months in the TMR group, whereas total exercise time and MVO2 were unchanged. No significant changes were observed in the MT group. Perioperative mortality was 4%. One year mortality was 12% in the TMR group and 8% in the MT group (p = NS.)
CONCLUSIONS
Transmyocardial laser revascularization was performed with low perioperative mortality and caused significant symptomatic improvement, but no improvement in exercise capacity.
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Abbreviations and Acronyms
| | CABG | = coronary artery bypass grafting | | CCS | = Canadian Cardiovascular Society | | ECG | = electrocardiogram | | LVEF | = left ventricular ejection fraction | | MI | = myocardial infarction | | MT | = medical treatment | | MVO2 | = maximal oxygen consumption | | NYHA | = New York Heart Association | | TMR | = transmyocardial laser revascularization |
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Despite improvements in medical therapy and conventional revascularization techniques, some patients with angina pectoris are left with severe symptoms refractory to medical treatment and without any possibility of using conventional revascularization methods because of diffuse and distal coronary artery disease. Transmyocardial laser revascularization (TMR) has been introduced as an alternative treatment for these patients (1,2). TMR is performed by making channels directly through the left ventricular wall with laser energy release by a left anterior thoracotomy approach (3). Observational clinical studies have shown that TMR can be performed with low operative risk, symptomatic effect in most patients, and improved quality of life (4-6). However, few randomized studies have been published (7-10), and high crossover rates was reported in two studies (8,9).
The mechanisms by which TMR acts are still unclear. The initial theory that channels remain open and perfuse the myocardium from the left ventricular cavity has little support in animal (11,12) and autopsy studies (13). Animal studies have shown that TMR can reduce infarct size, preserve contractile function (14), stimulate angiogenesis (15) and denervate the myocardium (16). There are conflicting results concerning the effect on myocardial perfusion from clinical studies (7,8,10,17). The aims of the present study were to evaluate clinical effects of TMR superimposed on optimal medical treatment in a randomized trial and the potential influence on exercise electrocardiogram (ECG) and maximal oxygen consumption (MVO2).
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Methods
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Study design.
The investigation was designed as an open, prospective, single center study. Following screening, adjustment of medication and a baseline evaluation, 100 eligible patients were randomized 1:1 using block-randomization into two comparable groups to achieve either continued optimal medical treatment alone (MT group), or optimal medical treatment in combination with transmyocardial revascularization with CO2-laser (TMR group). Included were patients who were suffering from angina pectoris New York Heart Association (NYHA) Functional Class III or IV despite optimal medical treatment, were not candidates for percutaneous transluminal coronary angioplasty or coronary artery bypass grafting (CABG) because of peripheral obstructions in the coronary arteries, and were willing to participate in a randomized study. Exclusion criteria were age >75 years, left ventricular ejection fraction (LVEF) < 30%, non-demonstrated reversible ischemia, overt heart failure, inability to undergo study tests and conditions precluding thoracic surgery. Follow-up evaluations were done after three and 12 months. The scientific protocol was approved by The Regional Ethics Committee.
Selection of patients.
Between November 1995 and January 1998, 226 patients referred from eight hospitals in Norway were evaluated for participation in the study (total population of Norway = 4.3 million). All patients had an earlier angiogram and had been refused for CABG or coronary angioplasty for technical reasons. The patients and angiograms underwent a screening for the study. For optimal evaluation, a new angiogram was required in 36 patients. Angina symptoms were classified according to NYHA. Angina classifications were done unblinded by one investigator after standardized interviews about symptoms related to graded activities. Reversible ischemia was assessed by exercise ECG, dobutamine stress-echo and technetium 99m (99mTc)–tetrofosmin myocardial perfusion scan (SPECT), as at least one of these methods should show reversible ischemia. LVEF was assessed by technetium 99m (99mTc) multiple-gated acquisition radionuclide ventriculography (MUGA). After re-evaluation, 103 patients were eligible for inclusion (Table 1), but three died before randomization was performed. Of those not randomized, 38 patients (17%) were offered conventional revascularization, one in combination with aortic valve replacement. The remaining 85 patients were excluded because of mild symptoms, non-demonstrated reversible ischemia, severely depressed LVEF, generally reduced health condition or refusal to participate in a randomized study. After inclusion, each patient received an allocation number. Randomization was then performed by opening consecutively numbered sealed envelopes with allocation numbers and treatment inside. One patient initially withdrew from the operation, but later changed his mind and was operated on three months after randomization; he has been followed up as patient who has received the operation. All other patients were operated on within two weeks after randomization. Evaluation, randomization and follow-up were done at The National Hospital.
Exercise protocol and maximal oxygen consumption analysis.
The test was performed on an electrically-braked cycle ergometer (Ergo-metrics 900; E. Jaeger, GmbH CoKG, Wurzenburg, Germany). The patients had abstained from medication, food, coffee and nicotinic consumption for 12 h prior to the test. Pedaling rate was kept at approximately 60 rotations/min with initial workload at 10 W, which increased by 10 W/min until the end of the test (defined as inability to continue because of chest pain, dyspnea or exhaustion, or a halt to the test because of blood pressure drop or arrhythmia). Maximal oxygen consumption was measured continuously by an open-circuit technique (Eos/Sprint; E. Jaeger, GmbH CoKG, Wurzenburg, Germany). Heart rate was recorded continuously by electrocardiography (Siemens Megacart; Siemens-Elema AB, Sweden) and a 12-channel ECG was printed out every 30 s. Blood pressure was measured non-invasively every minute using an automatic microphone transducer blood pressure recorder (Ergo-line; E. Jaeger, GmbH CoKG, Wurzenburg, Germany). Time until onset of chest pain, one millimeter of ST segment depression and termination of cycling were noted. Accumulated work (J = W x s) and double product (product of systolic blood pressure and heart rate/min) were calculated at maximal workload.
Predefined primary end points were time to one millimeter of ST segment depression and MVO2. Secondary end points were time to chest pain, total exercise time and accumulated work.
Surgical procedure.
All TMR operations were performed by the same surgeon at The Feiring Heart Clinic. Surgery was performed under combined general and thoracic epidural anesthesia without cardiopulmonary bypass. A single lumen tube was used and both lungs were inflated using an air–oxygen mixture free from nitrous oxide. Through a left anterior thoracotomy laser treatment was performed on the beating heart with an 800-W CO2-laser (The Heart Laser; PLC Medical Systems, Inc., Milford, Massachusetts, USA). The pulses were synchronized with R-wave in the ECG. The energy varied from 30 to 50 J, corresponding to a pulse duration of 30 to 50 ms. About one channel/cm2 of presumed ischemic and viable myocardium was made. Channel formation was confirmed and left ventricular function and possible laser-induced injuries to the submitral apparatus were assessed through a 5 MHz multiplanar ultrasound transesophageal probe (VingMed, Horten, Norway). Thoracic epidural analgesia was continued until the second postoperative day. Epicardial pacemaker electrodes, pericardial drainage and IV nitroglycerin were used as usual. Perioperative myocardial infarction (MI) was diagnosed by new Q-waves in the ECG, CK-MB isoenzyme values > 50 µg/l, serum gluatamic oxaloacetic transaminase (SGOT) > 100 U/l and a SGOT/serum glutamic pyruvic transaminase (SGPT) ratio > 2:1 within 30 days after surgery. Perioperative left ventricular dysfunction function was clinically diagnosed (inclusive of chest X-ray) when treatment with diuretics, inotropic agents or intra-aortic balloon pump was required. Acute renal failure was defined as at least a two-fold increase in serum creatinine.
Statistics.
Results are given as mean ± standard deviation (SD) or frequency (%). The evaluation of efficacy of TMR was done by estimating the relative changes (RC) in the outcome variables between baseline (OBL) and follow-up (OFU) [RC = (OBL – OFU / OBL) x 100] for each patient at three and 12 months. Comparisons of baseline values and relative changes between the two groups were done using the Student’s t-test and the Mann-Whitney non-parametric test. The power was estimated on the two surrogate end points, MVO2 and time to one millimeter of ST segment depression. We considered a relative improvement of 20% in MVO2 (an absolute improvement of 3 ml/kg/min compared to baseline for the TMR group versus no improvement in the MT group) and 24% in time to one millimeter of ST segment depression (absolute improvement of 100 s in the TMR group compared to baseline versus no improvement in the MT group) as clinically important. With 50 patients in each group and a type 1 error of 5%, the estimated power was 95% for relative change in MVO2 and the power was 87% for relative change in time to one millimeter of ST segment depression. Significance level was defined as p < 0.05 (18). Analysis was performed in SPSS for Windows, version 7.5.2.
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Results
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Need for TMR.
Patients came from all parts of Norway, but the majority came from health region 2 with a population of 1.6 million people. Most patients with severe angina who were not candidates for conventional revascularization from this region were probably evaluated for inclusion in the randomized TMR protocol. Over the course of 27 months, 76 patients were accepted for the study from this region. Thus, according to our criteria, a request for isolated TMR of about 21 patients/million people/yr can be assumed. If we include patients who refused participation in the study, the figure would be 24 patients/million people/yr.
Baseline characteristics.
Except that the double product at maximal exercise was higher in the TMR group than in the MT group at baseline (p < 0.05), there were no significant differences between the treatment groups (Table 2). Twenty-eight patients were classified to NYHA functional class IV and 72 to functional class III. No patient was unstable with increased symptoms during the week prior to the beginning of the study. Mean age for the whole group was 62.5 years (SD 3.2), and 14% were women. The severity of the disease is underlined by the risk profiles, concomitant diseases and number with earlier myocardial infarction and revascularization. Mean LVEF was 49%. The groups did not differ significantly with regard to the extent of reversible ischemia or fixed defects as assessed by the various methods (Table 3). Ninety-five percent of the patients were treated with beta blocker therapy and the majority received long acting nitrates and Ca channel blockers as well (Table 4).
Surgical data and perioperative results.
An average of 48 ± 7 channels were made. During surgery one patient was found to have a graftable left anterior descending coronary artery (LAD) not detected by angiography. In addition to TMR, this patient received a left internal mammary artery graft to the LAD without cardiopulmonary bypass, and was therefore excluded from follow-up analyses. Four patients suffered perioperative MI. Two patients (4%) died after 4 and 14 days, respectively, from left ventricular failure in spite of inotropic medication, intra-aortic balloon pump and respiratory support. Autopsies showed an inferior and septal infarction in the first patient and an inferior infarction in the second patient, and no patent channels were observed. These patients were in preoperative functional class IV, with unprotected three-vessel disease. LVEF was 57% and 30%, respectively. Two additional patients had MI: one was treated for 44 days in the intensive care unit with respiratory support and was discharged for home care after 56 days, and the other had an uncomplicated anterior MI and was discharged after 11 days. Seventeen patients (35%) were treated for perioperative heart failure. Four patients had pulmonary infections, and two of these needed temporary respiratory support. Mean hospital stay was 11.1 ± 8.6 days with a median of 8.0 (7–56), and mean intensive care unit stay was 2.9 ± 6.2 days with a median of 2.0 (1–44).
Clinical result at follow-up.
Mortality and morbidity
Follow-up of patients after three and 12 months was complete. However, one patient in each group did not perform the exercise tests after 12 months: one because of a cerebral hemorrhage and inability to perform tests and one for personal reasons. They were interviewed by telephone about symptoms, but otherwise excluded from result analysis after 12 months. In addition to the two (4%) early postoperative deaths, four patients in each group died within one year of the randomization date. In the TMR group one patient died from cancer, one from intracerebral hemorrhage and two died suddenly. In the MT group one death was caused by septicemia, one by acute MI, one by clinical heart failure and one patient died suddenly. There were no significant differences in hospitalizations during the first year. In the TMR group there were 40 hospitalizations, including 17 from unstable angina and 1 from acute MI. In the MT group there were 45 hospitalizations, including 19 from unstable angina and 1 from acute MI.
Symptomatic effects
In the TMR group, 63% experienced an improvement of one or more functional classes after three months, and 29% experienced an improvement of two or more classes (Table 5). After 12 months, 71% had improved by one or more functional classes, and 39% had improved by two or more classes. Mean functional class was 3.3 at baseline, 2.3 at three months and 2.0 at 12 months. In the MT group, there were no significant changes in symptoms. Details are shown in Figures 1 and 2.
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Figure 1 Angina symptoms in the transmyocardial revascularization group. Circles with numbers indicate number of patients. Arrows with numbers indicate how many and how patients have changes in symptoms during follow-up.
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Exercise tests
(Table 5) Time to chest pain during the bicycle stress test increased in the TMR group by 78 ± 118 s and 66 ± 104 s compared to baseline values after three and 12 months, respectively. Comparing the relative changes in the two groups, this was significant after 12 months (p < 0.01), but not after three months. Angina was reported as limiting exercise factor in fewer patients in the TMR group after three (n = 28) and 12 months (n = 26) compared to baseline (n = 44). This was statistically significant compared to baseline values and to the relative change in the MT group (p < 0.01). There were no clinically or statistically significant differences between the relative changes in outcome values between the groups for time to one millimeter of ST segment depression, double product, total exercise time or MVO2.
Medical treatment
An increased use of angiotensin-converting enzyme (ACE) inhibitors and diuretics and a reduced use of aspirin was observed in the TMR group during follow-up. The changes were statistically not significant (p >0.08). Otherwise, only minor changes occurred in medications (Table 4).
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Discussion
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Symptoms.
The main finding in the present study was a significant symptomatic improvement after TMR in many patients lasting for at least one year. An improvement of two or more functional classes was experienced by 29% and 39% of the patients in the TMR group after three and 12 months, respectively. This is comparable with the reports from Schofield et al. (7), but somewhat lower than reported in other studies (5,8,10). In our study, symptoms were classified using NYHA classification, which influences comparison to other studies using CCS classification. Patients in CCS class 1 are allowed to have light symptoms, which is not the case in the NYHA classification. Consequently, more patients in CCS class III than in NYHA class III at baseline are able to improve by two functional classes. An improvement of one functional class may be considered as clinically unimportant. However, such improvement was reported by our patients as an important relief from symptoms. In the MT group no clinically important or statistically significant change was observed.
Placebo effects are expected to contribute substantially to symptom relief when there are high expectations for the treatment. In an open trial, even if randomized, doctor and patient bias must be taken into consideration. Burkhoff et al. (10) showed differences in angina score as given by an investigator and an independent observer, while Frazier et al. (8) did not find significant differences in scoring between observers. Symptoms were classified after a standardized activity-related interview in our study. Unblinded assessment may, however, represent a weakness. One would expect placebo effects to diminish over time. It has been argued that denervation may explain early symptom relief (16) and neoangiogenesis late improvement (15) after TMR. There are variable reports on the development of late symptoms after TMR (5–7). The improvement in symptoms from three to 12 months in our study was statistically not significant and may be explained by spontaneous variations in the disease. In our trial we used two surrogate end points (SEP). Usually, this kind of trial is designed to determine whether intervention is biologically active and whether to perform further large clinical trials with MI and cardiac-related mortality as clinically important end points. Our trial with SEP is equivalent to animal models, and must be used with great caution in making clinical decisions (19).
Exercise tests.
At follow-up, time to chest pain during exercise increased significantly and fewer patients were limited by chest pain in the TMR group, while no significant change was seen in the MT group. This is in accordance with results from other studies (4,6,7,10,17). In contrast to reports from two recently published studies with Holmium laser (9,10), exercise capacity was not improved in our study. Thirty-eight percent of the patients in the TMR group were limited by symptoms other than chest pain during follow-up (mainly dyspnea), as described by others (7,17). Maximal oxygen consumption did not change during follow-up in either group, and such a change in MVO2 has not been reported in comparable studies. The deconditioned condition of the study patients is reflected by the low MVO2, with many in the range where heart failure patients may be evaluated for heart transplantation (20). Donovan et al. (21) reported reduced ischemic wall motion abnormalities after TMR. It may be that exercise capacity and MVO2 are not sensitive enough to detect small functional improvements in deconditioned patients. Time to one millimeter of ST segment depression increased only slightly in the TMR group after 12 months (p = NS), and was considered clinically unimportant.
Follow-up was complete and crossover was not allowed. This will make for more reliable results in comparison with studies with lower follow-up proportions and crossover design. In Norway, bicycle exercise test is commonly used as the standard. However, walking tests and treadmill tests may be easier to perform, and thus more sensitive in reflecting improvements in patients who have adapted to a quiet life over many years. Secondary metabolic changes in peripheral muscles due to reduced activity have been described in heart failure patients (22) and may contribute to the lack of improvement.
Medical treatment.
During the planning of the study there was no available answer to the question of whether or not TMR could cause a reduction in myocardial ischemia. We therefore considered it to be of potential risk for the patients to change from symptomatic to more silent ischemia, and reduction in anti-ischemic therapy was not intended in either group during follow-up. The patients were informed of the reason for not reducing medications. This could reduce expectations and placebo effects on the one hand, but on the other hand should not decrease the treatment effects compared with other studies. In addition, some patients (p = NS) in the TMR group stopped taking aspirin due to side-effects, which could affect the results.
Mortality and morbidity.
Postoperative mortality was low (4%) and comparable to the results reported by Schofield et al. (7), Hughes (23), Krabatsch (17) and Burkhoff (10), but favorable compared to other published studies (5,6,8,24). We believe this was due to the strict selection criteria, especially the exclusion of patients of advanced age, LVEF below 30% and unstable angina, which have been shown to predict higher mortality (6,8,25). Apart from the postoperative deaths there was no difference in one-year mortality between the groups. Our study was not designed to evaluate late mortality (> 30 days) and these data should therefore be interpreted with caution.
A mean of 47 channels, which is higher than in other published studies (n = 23–37) with CO2-laser (5–8,24), means that with 1 channel/cm2 an average of 49 cm2 of myocardium was treated. The optimal number of channels has not been established. We report an incidence of early postoperative heart failure (35%) that is higher than some studies (5–8), but comparable to what is reported by Hughes et al. (23). It has been shown (25) that TMR can cause left ventricular dysfunction in the early postoperative period, and that different mechanisms may be responsible (26,27). Whether the number of channels is an important factor in this respect is uncertain. The criteria for diagnosing postoperative heart failure are not clearly defined in some other studies and may vary from center to center. Consequently, the reported incidence of heart failure may differ between studies.
Postoperative morbidity was comparable to that reported by Hughes et al. (23). It is noteworthy, however, that only 40% of the patients had an uncomplicated postoperative course, underscoring the seriousness of the surgical trauma. The increased use of ACE inhibitors and diuretics (p = NS) observed in the TMR group could indicate an increase in late heart failure. However, LVEF (MUGA) decreased only slightly and no increase in heart failure hospitalization was observed.
In contrast to other studies, we found no differences in hospital admissions during follow-up. This may partly be explained by lower numbers of hospital admissions in both groups than reported by others (5,7). Geography, reduced hospital availability and the intensive drug treatment in our patients may represent other explanations.
Seventeen percent of our patients judged not to be candidates for traditional revascularization were after re-evaluation found to be eligible for coronary angioplasty or CABG. This is consistent with other reports and underscores the importance of re-evaluating patients when no revascularization therapy seems possible. However, some patients will be in need of supplementary therapies.
Conclusions.
In the present study, TMR was shown to be effective in relieving symptoms, whatever the mechanisms may be. Transmyocardial revascularization with laser is primarily a symptomatic treatment, and so far there is no convincing evidence of either improved myocardial function or a reduced number of ischemic events. Therefore, the term "heart laser treatment" may be a more appropriate term than "transmyocardial revascularization". With proper selection of patients, we believe these operations can be performed reasonably safely, but the risk for perioperative mortality and significant morbidity should not be neglected when selecting patients. Whether new technology using percutaneous transarterial access (PMR) is similarly effective and reduces patient risk should be evaluated through properly planned studies in the future. To further evaluate placebo effects of TMR, results from double-blind, placebo-controlled studies with PMR are awaited.
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Footnotes
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This study was supported by grants from the Norwegian Ministry of Health and Social Affairs.
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E. H. Yang, G. W. Barsness, B. J. Gersh, K. Chandrasekaran, and A. Lerman
Current and Future Treatment Strategies for Refractory Angina
Mayo Clin. Proc.,
October 1, 2004;
79(10):
1284 - 1292.
[Abstract]
[PDF]
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J. A. P. van der Sloot, M. Huikeshoven, R. Tukkie, H. J. Verberne, J. van der Meulen, B. L. F. van Eck-Smit, M. J. C. van Gemert, J. G. P. Tijssen, and J. F. Beek
Transmyocardial revascularization using an XeCl excimer laser: Results of a randomized trial
Ann. Thorac. Surg.,
September 1, 2004;
78(3):
875 - 881.
[Abstract]
[Full Text]
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K. B. Allen, R. D. Dowling, D. R. Schuch, T. A. Pfeffer, S. Marra, E. A. Lefrak, T. L. Fudge, M. Mostovych, S. Szentpetery, S. P. Saha, et al.
Adjunctive transmyocardial revascularization: five-year follow-up of a prospective, randomized trial
Ann. Thorac. Surg.,
August 1, 2004;
78(2):
458 - 465.
[Abstract]
[Full Text]
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K. B. Allen, R. D. Dowling, and W. Richenbacher
From controlled trials to clinical practice: monitoring transmyocardial revascularization use and outcomes
J. Am. Coll. Cardiol.,
June 16, 2004;
43(12):
2364 - 2365.
[Full Text]
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K. B. Allen, R. D. Dowling, W. W. Angell, D. M. Gangahar, T. L. Fudge, W. Richenbacher, S. L. Selinger, M. R. Petracek, and D. Murphy
Transmyocardial revascularization: 5-year follow-up of a prospective, randomized multicenter trial
Ann. Thorac. Surg.,
April 1, 2004;
77(4):
1228 - 1234.
[Abstract]
[Full Text]
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C. R. Bridges, K. A. Horvath, W. C. Nugent, D. M. Shahian, C. K. Haan, R. J. Shemin, K. B. Allen, and F. H. Edwards
The Society of Thoracic Surgeons practice guideline series: transmyocardial laser revascularization
Ann. Thorac. Surg.,
April 1, 2004;
77(4):
1494 - 1502.
[Abstract]
[Full Text]
[PDF]
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J. F. Beek, J. A. P. van der Sloot, M. Huikeshoven, H. J. Verberne, B. L. F. van Eck-Smit, J. van der Meulen, J. G. P. Tijssen, M. J. C. van Gemert, and R. Tukkie
Cardiac denervation after clinical transmyocardial laser revascularization: Short-term and long-term iodine 123-labeled meta-iodobenzylguanide scintigraphic evidence
J. Thorac. Cardiovasc. Surg.,
February 1, 2004;
127(2):
517 - 524.
[Abstract]
[Full Text]
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E. D. Peterson, P. Kaul, R. G. Kaczmarek, B. G. Hammill, P. W. Armstrong, C. R. Bridges, T. B. Ferguson Jr, and Society of Thoracic Surgeons
From controlled trials to clinical practice: monitoring transmyocardial revascularization use and outcomes
J. Am. Coll. Cardiol.,
November 5, 2003;
42(9):
1611 - 1616.
[Abstract]
[Full Text]
[PDF]
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M. Loubani, D. Chin, J. N. Leverment, and M. Galinanes
Mid-term results of combined transmyocardial laser revascularization and coronary artery bypass
Ann. Thorac. Surg.,
October 1, 2003;
76(4):
1163 - 1166.
[Abstract]
[Full Text]
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M. Saririan and M. J. Eisenberg
Myocardial laser revascularization for the treatment of end-stage coronary artery disease
J. Am. Coll. Cardiol.,
January 15, 2003;
41(2):
173 - 183.
[Abstract]
[Full Text]
[PDF]
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R. J. Gibbons, J. Abrams, K. Chatterjee, J. Daley, P. C. Deedwania, J. S. Douglas, T. B. Ferguson Jr, S. D. Fihn, T. D. Fraker Jr, J. M. Gardin, et al.
ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina--Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina)
Circulation,
January 7, 2003;
107(1):
149 - 158.
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Committee Members, R. J. Gibbons, J. Abrams, K. Chatterjee, J. Daley, P. C. Deedwania, J. S. Douglas, T. B. Ferguson Jr, S. D. Fihn, T. D. Fraker Jr, et al.
ACC/AHA 2002 guideline update for the management of patients with chronic stable angina--summary article: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina)
J. Am. Coll. Cardiol.,
January 1, 2003;
41(1):
159 - 168.
[Full Text]
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M. Ruel, R. A. Kelly, and F. W. Sellke
Therapeutic Angiogenesis, Transmyocardial Laser Revascularization, and Cell Therapy
Card. Surg. Adult,
January 1, 2003;
2(2003):
715 - 750.
[Full Text]
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M. Huikeshoven, J. F. Beek, J. A.P. van der Sloot, R. Tukkie, J. van der Meulen, and M. J.C. van Gemert
35 years of experimental research in transmyocardial revascularization: what have we learned?
Ann. Thorac. Surg.,
September 1, 2002;
74(3):
956 - 970.
[Abstract]
[Full Text]
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L. Aaberge, K. Rootwelt, S. Blomhoff, K. Saatvedt, M. Abdelnoor, and K. Forfang
Continued symptomatic improvement three to five years after transmyocardial revascularization with co2 laser: A late clinical follow-up of the norwegian randomized trial with transmyocardial revascularization
J. Am. Coll. Cardiol.,
May 15, 2002;
39(10):
1588 - 1593.
[Abstract]
[Full Text]
[PDF]
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G. C. Hughes, S. S. Biswas, B. Yin, D. V. Baklanov, B. H. Annex, R. E. Coleman, T. R. DeGrado, C. K. Landolfo, K. P. Landolfo, and J. E. Lowe
A comparison of mechanical and laser transmyocardial revascularization for induction of angiogenesis and arteriogenesis in chronically ischemic myocardium
J. Am. Coll. Cardiol.,
April 3, 2002;
39(7):
1220 - 1228.
[Abstract]
[Full Text]
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C. Mannheimer, P. Camici, M.R. Chester, A. Collins, M. DeJongste, T. Eliasson, F. Follath, I. Hellemans, J. Herlitz, T. Luscher, et al.
The problem of chronic refractory angina. Report from the ESC Joint Study Group on the Treatment of Refractory Angina
Eur. Heart J.,
March 1, 2002;
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[Full Text]
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R. J. Laham, M. Simons, J. D. Pearlman, K. K. L. Ho, and D. S. Baim
Magnetic resonance imaging demonstrates improved regional systolic wall motion and thickening and myocardial perfusion of myocardial territories treated by laser myocardial revascularization
J. Am. Coll. Cardiol.,
January 2, 2002;
39(1):
1 - 8.
[Abstract]
[Full Text]
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S. B. Freedman and J. M. Isner
Therapeutic Angiogenesis for Coronary Artery Disease
Ann Intern Med,
January 1, 2002;
136(1):
54 - 71.
[Abstract]
[Full Text]
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J. M. Isner, P. R. Vale, J. F. Symes, and D. W. Losordo
Assessment of Risks Associated With Cardiovascular Gene Therapy in Human Subjects
Circ. Res.,
August 31, 2001;
89(5):
389 - 400.
[Abstract]
[Full Text]
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P. R. Vale, D. W. Losordo, C. E. Milliken, M. C. McDonald, L. M. Gravelin, C. M. Curry, D. D. Esakof, M. Maysky, J. F. Symes, and J. M. Isner
Randomized, Single-Blind, Placebo-Controlled Pilot Study of Catheter-Based Myocardial Gene Transfer for Therapeutic Angiogenesis Using Left Ventricular Electromechanical Mapping in Patients With Chronic Myocardial Ischemia
Circulation,
May 1, 2001;
103(17):
2138 - 2143.
[Abstract]
[Full Text]
[PDF]
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M. J. Post, R. Laham, F. W. Sellke, and M. Simons
Therapeutic angiogenesis in cardiology using protein formulations
Cardiovasc Res,
February 16, 2001;
49(3):
522 - 531.
[Abstract]
[Full Text]
[PDF]
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D. W. Losordo, P. R. Vale, R. C. Hendel, C. E. Milliken, F. D. Fortuin, N. Cummings, R. A. Schatz, T. Asahara, J. M. Isner, and R. E. Kuntz
Phase 1/2 Placebo-Controlled, Double-Blind, Dose-Escalating Trial of Myocardial Vascular Endothelial Growth Factor 2 Gene Transfer by Catheter Delivery in Patients With Chronic Myocardial Ischemia
Circulation,
April 30, 2002;
105(17):
2012 - 2018.
[Abstract]
[Full Text]
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Abstract
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